JP5063351B2 - Pyrazole kinase modulator and methods of use - Google Patents

Description

(Cross-reference of related applications)
This application claims priority from US Provisional Patent Application No. 60 / 610,689, which was filed on September 17, 2004. The contents of the prior application are incorporated herein by reference in their entirety.

(Field of Invention)
The present invention relates to compounds for modulating protein kinase enzyme activity to modulate cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. More specifically, the present invention relates to compounds that inhibit, regulate and / or modulate kinases, particularly Kit and flt-3. Kinase receptor signaling pathways associated with changes in cellular activity as described above are modulated using the compounds of the present invention. Methods of using them to treat kinase dependent diseases and conditions are also aspects of the invention.

(Overview of related technologies)
The improvement in the specificity of the factors used to treat cancer is of considerable interest due to the therapeutic benefit of determining whether the side effects associated with the administration of these factors are reduced. Traditionally, dramatic improvements in the treatment of cancer have been associated with the identification of therapeutic factors that act through novel mechanisms.

  Protein kinases are enzymes that catalyze the phosphorylation of proteins, particularly the hydroxy groups of tyrosine, serine and threonine residues of proteins. The result of this seemingly simple activity is staggering; cell differentiation and proliferation; that is, virtually all aspects of cell life are in any case dependent on protein kinase activity. Moreover, aberrant protein kinase activity is associated with a host of disorders ranging from relatively life-threatening diseases such as psoriasis to highly pathogenic diseases such as glioblastoma (brain tumor).

  Protein kinases can be classified as receptor type or non-receptor type. Receptor tyrosine kinases have an extracellular portion, a transmembrane portion, and an intracellular portion, whereas non-receptor tyrosine kinases are entirely intracellular.

  Receptor tyrosine kinases include a large number of transmembrane receptors with diverse cytological activities. In fact, about 20 different subfamilies of receptor tyrosine kinases have been identified. One tyrosine kinase subfamily (named HER subfamily) is composed of EGFR (HER1), HER2, HER3, and HER4. The ligands of this receptor subfamily that have been identified to date include epidermal growth factor, TGF-α, amphiregulin, HB-EGF, β-cellulin and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, including INS-R, IGF-IR, and IR-R. The PDGF subfamily includes PDGF-α receptor and PDGF-β receptor, CSFIR, c-kit and FLK-II. Next, FLK composed of kinase insertion domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and fms-like tyrosine kinase-1 (Flt-1) There is a family. The PDGF family and FLK family are usually considered similarly because of the similarity of the two groups. See Non-Patent Document 1 for a detailed description of the receptor tyrosine kinase. This is incorporated herein by reference.

  Non-receptor tyrosine kinases are also composed of a number of subfamilies (including Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack, and LIMK). Each of these subfamilies is further sub-divided into a variety of receptors. For example, the Src subfamily is one of the largest subfamilies and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. The Src subfamily of enzymes is associated with tumorigenesis. See Non-Patent Document 2 for a more detailed description of non-receptor tyrosine kinases. This is incorporated herein by reference.

  Since protein kinases and their ligands play an important role in a variety of cellular activities, deregulation of protein kinase enzyme activity may result in altered cellular properties (eg, unregulated cell growth associated with cancer). Can lead to. In addition to oncological signs, altered kinase signaling is implicated in many other pathological diseases. These include, but are not limited to: immune disorders, cardiovascular diseases, inflammatory diseases, and degenerative diseases. Thus, both receptor protein kinases and non-receptor protein kinases are attractive targets for small molecule drug discovery.

  One attractive goal for therapeutic use of kinase modulation is related to oncological signs. For example, the modulation of protein kinase activity for the treatment of cancer is the FDA-approved Gleevec® (Imanitib) for the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal cancer (GIST). Mesylate, manufactured by NJ's East Hanover, Novartis Pharmaceutical Corporation). Gleevec is a c-Kit and Ab1 kinase inhibitor.

  With respect to the regulation (particularly inhibition) of cell proliferation and angiogenesis, two important cellular processes required for tumor growth and survival (Non-Patent Document 3) are fascinating for the development of small molecule drugs. Goal. Anti-angiogenic treatment is powerfully important for the treatment of solid tumors and other diseases associated with unregulated angiogenesis (including ischemic coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis) Represents an approach. Similarly, cellular anti-proliferative factors are desirable to slow or stop tumor growth.

  One particular interesting target for small molecule regulation is c-Kit. Proto-oncogene c-Kit was first identified as the oncogene component of Hardy-Zuckerman 4-cat sarcoma virus that rapidly undergoes canceration (Non-Patent Document 4). c-Kit (also referred to as stem cell factor receptor or steel factor receptor) is a type 3 receptor tyrosine kinase (RTK) belonging to the subfamily of platelet derived growth factor receptors. c-Kit binds to the ligand stem cell factor (SCF) and triggers multiple signaling pathways including Src family kinases (phosphatidyl-inositol 3 kinase, Ras-Raf-Map kinase cascade, and phospholipase C) ( Non-patent document 5; Non-patent document 6; Non-patent document 7; Non-patent document 8; Non-patent document 9; Non-patent document 10; Non-patent document 6; c-Kit is required for normal hematopoiesis, melanogenesis, and gametogenesis. c-Kit is expressed in mast cells, immature myeloid cells, melanocytes, mammary epithelial cells and calcinous stromal cells (ICC). In mast cells, this is required not only for differentiation, mutation, chemotaxis, and chemotaxis, but also for promoting survival and proliferation.

  Mutations in c-Kit have been implicated in human diseases. Mutations in the near membrane domain are found in many human gastrointestinal stromal tumors, and mutations in the kinase domain include mastocytosis, germ cell tumors, acute myeloid leukemia (AML), NK cell lymphoma, And other hematological diseases (Non-patent document 13; Non-patent document 14; Non-patent document 15; Non-patent document 16; Non-patent document 17; Non-patent document 18). These mutations result in ligand-independent tyrosine kinase activity, c-Kit autophosphorylation, unregulated cell growth, and stimulation of downstream signaling pathways. Overexpression of c-Kit and c-Kit ligand has also been described in other tumors including small cell lung cancer, neuroblastoma, gynecological tumors, and colon cancer, which are autocrine c- Kit activation or paracrine c-Kit activation can occur.

  c-Kit overexpression has also been implicated in the development of neoplasia associated with neurofibromatosis type 1 (NF1). Mutations in the tumor suppressor gene NF1 result in a deficiency in neurofibromin (GTPase activating gene for Ras). This defect results in abnormal proliferation of Schwann cells in the peripheral nervous system, and affects affected individuals in peripheral nerve sheath tumors (neurofibromatosis), astrocytomas (optical path glioma), learning There is a tendency to fall into disorder, stroke, stroke, macrocranial disease, vascular abnormalities, and juvenile myelomonocytic leukemia (Non-patent Document 19). Genetic experiments in mice have demonstrated that haploinsufficiency in NF1 partially rescues some of the phenotypes related to mutations in the gene for c-Kit, indicating that these genes are generally It shows that it functions along a generation | occurrence | production path | route (nonpatent literature 20). C-Kit is expressed in schwannoma cells derived from NF1 patients, but not in normal Schwann cells (Non-patent Document 21). These data indicate that high c-Kit expression and high sensitivity to stem cell factor may play an important role in the development of proliferative disorders related to NF-1. Thus, c-Kit inhibitors may be effective chemotherapeutic agents for treating patients with NF-1.

  GISTs are the most common mesenchymal tumors of the gastrointestinal tract, and they are generally resistant to chemotherapy and radiation therapy. However, recent results with the c-Kit / BCR-Abl inhibitor STI571 indicate that c-Kit targeting can be an effective therapeutic strategy for this disease (Non-Patent Document 22). Malignant mast cell disease often shows a very poor prognosis and no reliable and effective chemotherapeutic agent has been identified (Non-patent Document 23). Systemic mast cell disorders have been treated with interferon-α, but the effectiveness of this therapy is subject to change (Non-patent document 24; Non-patent document 25). Thus, activated c-Kit may serve as a therapeutic target in GIST and mast cell diseases, as well as other disorders associated with activated c-Kit.

flt-3 is normally expressed in hematopoietic progenitor cells and a subset of mature myeloid and mature lymphoid cells, where it regulates cell survival and proliferation. flt-3 is constitutively activated through mutations in either the near-membrane region or the activation loop of the kinase domain in the majority of patients with AML (Non-Patent Document 26). Also, mutations in flt-3 are significantly correlated with poor prognosis in AML patients. (Non-patent document 27).
Plowman et al., DN & P 7 (6): 334-339, 1994. Bolen, Oncogene, 8: 2025-2031 (1993) Matter A. Drug Disc Technol 2001 6, 1005-1024 Besmer et al., Nature, 1986, 320, p. 415-421 Bloody et al., Blood, 1999, 94, p. 1979-1986 Lennartsson et al., Oncogene, 1999, 18, p. 5546-5553 Timokina et al., EMBO J, 1998, 17, p. 6250-6262 Chian et al., Blood, 2001, Vol. 98, No. 5, p. 1365-1373 Blume-Jensen et al., Curr Biol, 1998, Vol. 8, p. 779-782 Kissel et al., EMBO J, 2000, Vol. 19, p. 1312-1326 Sue et al., Blood, 1998, Vol. 92, p. 1242-1149 Lev et al., EMBO J, 1991, Volume 10, p. 647-654 Hirota et al., Science, 1998, 279, p. 577-580 Singer et al., J Clin Oncol, 2002, p. 203898-3905 Longley et al., Proc Natl Aca Sci USA, 1999, p. 1609-1614 Tian et al., Am J Pathol, 1999, 154, p. 1643-1647 Beghini et al., Blood, 2000, 95, p. 726-727 Hongyo et al., Cancer Res, 2000, 60, p. 2345-2347 Lynch and Gutmann, Neurol Clin, 2002, Volume 20, p. 841-865 Ingram et al. Exp Med, 2000, Vol. 191, p. 181-187 Ryan et al., J Neurosci Res, 1994, 37, p. 415-432 Eisenberg and Mehren, Expert Opin Pharmacother, 2003, Volume 4, p. 869-874 Marone et al., Leuk Res, 2001, 25, p. 583-594 Lehmann and Lammle, Ann Hematol, 1999, vol. 78, p. 483-484 Butterfield Br, J Dermatol, 1998, Vol. 138, p. 489-495 Reilly, Leuk Lymphoma, 2003, 44, p. 1-7 Sawyers, Cancer Cell, 2002, Volume 1, p. 413-415

  Thus, the identification of small molecule compounds that specifically inhibit, control and / or modulate the above signaling of kinases (particularly c-Kit and flt-3) is the treatment or prevention of disease states associated with abnormal cell proliferation. This is desirable as a means of the present invention.

(Summary of the Invention)
In one aspect, the present invention is described herein for treating compounds mediated by c-Kit and flt-3 kinase activity, and diseases mediated by c-Kit and flt-3 activity. Methods utilizing the prepared compounds and pharmaceutical compositions are provided. Diseases mediated by c-Kit and flt-3 activity include diseases characterized in part by migration, invasion, proliferation, and other biological activities associated with invasive cell growth. However, it is not limited to these.

  In another aspect, the present invention provides a screening method for modulators of c-Kit and flt-3 activity. The method comprises combining the composition of the present invention, c-Kit or flt-3 with at least one candidate factor, and determining the effect of the candidate factor on the c-Kit or flt-3 activity Is included.

  In yet another aspect, the present invention also provides one or more components of the pharmaceutical compounds and / or pharmaceutical compositions of the present invention (one or more c-Kit as described herein). Or a pharmaceutical kit comprising one or more containers filled with a modulator of flt-3 enzyme activity). Such kits also regulate other compounds and / or compositions (eg, diluents, penetration enhancers, scales, etc.), devices for administering the compounds and / or compositions, and manufacture, for example. May include instructions written in a form prescribed by government agencies (use or sale of pharmaceutical or biological products) that also relate to manufacture, use or sale for human administration May indicate agency approval.

  In yet another aspect, the present invention also provides a diagnostic agent comprising a compound of the present invention and, optionally, pharmaceutically acceptable adjuvants and excipients.

  These and other features and advantages of the present invention are described in more detail below, with reference to the associated drawings.

(Detailed description of the invention)
The compositions of the invention are used to treat diseases associated with abnormal cell activity and / or unregulated cell activity. Disease states that can be treated by the methods and compositions provided herein include cancer (discussed further below), immunological disorders (eg, rheumatoid arthritis, graft-host disease, multiple disease Sclerosis, psoriasis); cardiovascular diseases (eg, arteriosclerosis, myocardial infarction, ischemia, stroke, and restenosis); other inflammatory and degenerative diseases (eg, gut disease (eg, interbowel diseases), osteoarthritis, macular degeneration, diabetic retinopathy), but are not limited thereto.

  In some cases, it is understood that the cells may not be in excess or reduced, proliferative and / or mobile (abnormal) state and require further treatment. For example, during wound healing, the cells may be “normally” growing, but increased proliferation and migration may be desired. Alternatively, a decrease in “normal” cell growth rate and / or “normal” cell migration rate may be desired.

  The present invention includes compounds according to Formula I that modulate kinase activity, particularly c-Kit and / or flt-3, or pharmaceutically acceptable salts, hydrates or prodrugs thereof:

here,
R ¹ and R ² are each independently —H, halogen, haloalkyl, haloalkoxy, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _0-2. R ³ , —N (R ³ ) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (═O) C (═O) N (R ³ ) R ³ , —SO ₂ N _{^{(R 3) R 3, -CO}} 2 R 3, -C (= O) N (R 3) R 3, -C (= NR 5) N (R 3) R 3, -C (= NR 5) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —NCO ₂ R ³ , —N (R ³ ) C (O) ₂ R ³ , —C (= O) R ^3, substituted alkoxy optionally substituted lower alkyl optionally substituted aryl optionally lower arylalkyl optionally substituted, optionally substituted Cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl Selected from;
each of m and n is independently 1-5;
Each of A and B is independently selected from 5- to 10-membered aryl or heteroaryl;
R ³ is —H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclyl, Selected from alkyl;
Two of R ³ can be combined with the nitrogen to which they are attached to combine to form an optionally substituted heterocyclyl, which contains between 1 and 3 additional heteroatoms. Do;
R ⁴ is selected from —H or optionally substituted lower alkyl;
Each R ⁵ is independently -H, -CN, -NO ₂ , -OR ³ , -S (O) _0-2 R ³ , -CO ₂ R ³ , optionally substituted lower alkyl, optionally Selected from optionally substituted lower alkenyl, and optionally substituted alkynyl; and each of L ¹ and L ² is independently absent or from —C (R ³ ) ═C (R ³ ) — Selected;
However, the compound is N ′-[3- [5- (3-chlorophenyl) -1H-pyrazol-3-yl] phenyl] -N, N-dimethyl-urea (registration number 143704-64-7) or N '-[3- [5- (2-Chlorophenyl) -1H-pyrazol-3-yl] phenyl] -N, N-dimethyl-urea (registration number 143704-63-6), but not The compound does not conform to formula i,

Where R is lower alkyl or optionally substituted phenyl; and Y is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, N, N-dialkylamino, and N-lower alkyl-N -Lower alkoxyamino.

In one example, the compound is in accordance with International Publication No. [0023], such as alkoxy, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl. Substituents are optionally substituted with one or more substituents, which are independently alkyl, alkoxy, halo, haloalkyl, haloalkoxy, —CN, —NO ₂ , — OR ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —N (R ³ ) C (═O) N (R ³ ) R ³ , —N (R ³ ) C ( = O) C (= O) N (R ³ ) R ³ , -SO ₂ N (R ³ ) R ³ , -CO ₂ R ³ , -C (= O) N (R ³ ) R ³ , -C ( = N ^{5) N (R 3) R} 3, -C (= NR 5) R 3, -N (R 3) SO 2 R 3, -N (R 3) C (O) R 3, -NCO 2 R 3, —N (R ³ ) C (O) ₂ R ³ , —C (═O) R ³ , optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, required Selected from the group consisting of optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl Is done.

In one example, the compound conforms to International Publication No. [0023], wherein R ⁴ is —H.

In another example, the compound is according to International Publication ^No. [0036], wherein L ¹ and L ² are both —C (R ³ ) ═C (R ³ ) —.

In another example, the compound is in accordance with International Publication ^No. [0037], wherein L ¹ and L ² are both E—C (R ³ ) ═C (R ³ ) —.

  In another example, the compound is of formula II, according to paragraph [0038] of International Publication No.

Here, each of R ¹ and R ² is independently -H, halogen, haloalkyl, haloalkoxy, -CN, -NO ₂ , -OR ³ , -N (R ³ ) R ³ , -S (O). _{0 to 2} R ³ , —N (R ³ ) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (═O) C (═O) N (R ³ ) R ³ , − _{^{SO 2 N (R 3) R}} 3, -CO 2 R 3, -C (= O) N (R 3) R 3, -C (= NR 5) N (R 3) R 3, -C (= NR ⁵ ) R ³ , -N (R ³ ) SO ₂ R ³ , -N (R ³ ) C (O) R ³ , -N (R ³ ) C (O) ₂ R ³ , -NCO ₂ R ³ ,- C (= O) R ^3, alkoxy optionally substituted, lower alkyl optionally substituted, heteroaryl optionally substituted, cycloalkyl optionally substituted, necessary response Is selected from substituted aryl if the heterocyclyl or need replacement Te;
Each of A and B is a radical, and the radical is independently selected from the group consisting of phenyl, benzothiophenyl, pyridyl, pyrazinyl, benzofuranyl, benzopyrazolyl, benzoxazolyl, naphthyl, benzimidazolyl, indolyl, and biphenyl. .

  In another example, the compound is of Formula IIa according to WO [0039]

Here, each of R ¹ and R ² is independently -H, halogen, haloalkyl, haloalkoxy, -CN, -NO ₂ , -OR ³ , -N (R ³ ) R ³ , -S (O). _{0 to 2} R ³ , —N (R ³ ) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (═O) C (═O) N (R ³ ) R ³ , − _{^{SO 2 N (R 3) R}} 3, -CO 2 R 3, -C (= O) N (R 3) R 3, -C (= NR 5) N (R 3) R 3, -C (= NR ⁵ ) R ³ , -N (R ³ ) SO ₂ R ³ , -N (R ³ ) C (O) R ³ , -N (R ³ ) C (O) ₂ R ³ , -NCO ₂ R ³ ,- C (= O) R ^3, aryl optionally substituted, alkoxy optionally substituted, lower alkyl optionally substituted, heteroaryl optionally substituted, location as required The cycloalkyl, aryl substituted substituted heterocyclyl or optionally as necessary.

In another example, the compound is in accordance with WO [0042], wherein each of R ¹ and R ² is independently -H, halogen, haloalkyl, haloalkoxy, -CN, -NO ₂ , It is selected from —OR ³ , —N (R ³ ) R ³ , —C (═O) R ³ , or optionally substituted lower alkyl.

In another example, the compound is in accordance with International Publication ^No. [0043], wherein R ¹ is —H, halogen, haloalkyl, haloalkoxy, —CN, —NO ₂ , and optionally substituted lower And R ² is selected from —H, —OR ³ , —N (R ³ ) R ³ , or optionally substituted lower alkyl.

In another example, the compound is according to WO [0044], wherein R ¹ is selected from —H, halogen, haloalkyl or haloalkoxy; and R ² is —H, —OR ^3. , —N (R ³ ) R ³ , or optionally substituted lower alkyl.

  In another example, the compound is of formula III, according to International Publication No. [0045]

Wherein R ¹ is selected from —H, halogen, haloalkyl or haloalkoxy; and R ² is —H, —OR ³ , —N (R ³ ) R ³ , or optionally substituted lower Selected from alkyl.

In another example, the compound is in accordance with International Publication ^No. [0036], where L ¹ is absent and L ² is —C (R ³ ) ═C (R ³ ) —.

In another example, the compound is according to WO [0047], wherein L ¹ is absent and L ² is —C (H) ═C (H) —.

  In another example, the compound is of formula IV, according to International Publication No. [0048]

Here, each of R ¹ and R ² is independently -H, halogen, haloalkyl, haloalkoxy, -CN, -NO ₂ , -OR ³ , -N (R ³ ) R ³ , -S (O). _{0 to 2} R ³ , —N (R ³ ) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (═O) C (═O) N (R ³ ) R ³ , − _{^{SO 2 N (R 3) R}} 3, -CO 2 R 3, -C (= O) N (R 3) R 3, -C (= NR 5) N (R 3) R 3, -C (= NR ⁵ ) R ³ , -N (R ³ ) SO ₂ R ³ , -N (R ³ ) C (O) R ³ , -N (R ³ ) C (O) ₂ R ³ , -NCO ₂ R ³ ,- C (= O) R ^3, substituted alkoxy optionally heterocyclyl optionally substituted lower alkyl optionally substituted, aryl optionally substituted, location as required Each of A and B is a radical, which is separately phenyl, benzothiophenyl, pyridyl, pyrazinyl, benzofuranyl, naphthyl, Selected from benzimidazolyl, indolyl, or biphenyl.

  In another example, the compound is of formula IVa, according to WO [0049]

Here, each of R ¹ and R ² is independently -H, halogen, haloalkyl, haloalkoxy, -CN, -NO ₂ , -OR ³ , -N (R ³ ) R ³ , -S (O). _{0 to 2} R ³ , —N (R ³ ) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (═O) C (═O) N (R ³ ) R ³ , − _{^{SO 2 N (R 3) R}} 3, -CO 2 R 3, -C (= O) N (R 3) R 3, -C (= NR 5) N (R 3) R 3, -C (= NR ⁵ ) R ³ , -N (R ³ ) SO ₂ R ³ , -N (R ³ ) C (O) R ³ , -N (R ³ ) C (O) ₂ R ³ , -NCO ₂ R ³ ,- C (= O) R ^3, substituted alkoxy optionally heterocyclyl optionally substituted lower alkyl optionally substituted, aryl optionally substituted, location as required Heteroaryl, or optionally substituted cycloalkyl; and each A and B is a radical, which is separately phenyl, benzothiophenyl, pyridyl, pyrazinyl, benzofuranyl, benzopyrazolyl , Benzoxazolyl, naphthyl, benzimidazolyl, indolyl, and biphenyl.

  In another example, the compound is according to International Publication No. [0050], formula V;

Here, each of R ¹ and R ² is independently -H, halogen, haloalkyl, haloalkoxy, -CN, -NO ₂ , -OR ³ , -N (R ³ ) R ³ , -S (O). _0-2 R ³ , —CO ₂ R ³ , —C (═O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R ³ ) C (O) ₂ R ³ , —NCO ₂ R ³ , —C (═O) R ³ , optionally substituted alkoxy, optionally substituted heterocyclyl, optionally substituted Selected from lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted cycloalkyl; and A is a radical, said radical being phenyl, benzo Thiophenyl, pyridyl, benzofuranyl, benzo Imidazolyl or is selected from indolyl,.

  In another example, the compound is in accordance with International Publication No. [0051], where A is either phenyl or 2-benzimidazolyl.

In another example, the compound is in accordance with International Publication No. [0052], wherein A is —N (R ³ ) R ³ , optionally substituted heteroalicyclyl, or at least one lower alkyl. in is substituted, lower alkyl is substituted with at least one -N (R ³⁾ R 3.

In another example, the compound is according to WO [0036], where L ¹ and L ² are both absent.

  In another example, the compound is according to International Publication No. [0054], wherein A is 6-membered or 9-membered aryl or heteroaryl, and B is 6-membered aryl or heteroaryl.

  In another example, the compound is according to International Publication No. [0055], Formula VI,

Here, each of R ¹ , R ² and R ⁶ is independently -H, halogen, haloalkyl, haloalkoxy, -CN, -NO ₂ , -OR ³ , -N (R ³ ) R ³ , -S. (O) _0-2 R ³ , —N (R ³ ) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (═O) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (═S) N (R ³ ) R ³ , —SO ₂ N (R ³ ) R ³ , —CO ₂ R ³ , —C (═O) N (R ³ ) R ³ , —C (═NR ⁵ ) N (R ³ ) R ³ , —C (═NR ⁵ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R ³ ) C (O) ₂ R ³ , —NCO ₂ R ³ , —C (═O) R ³ , optionally substituted alkoxy, optionally substituted heterocyclyl, optionally Substituted lower al , Optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted cycloalkyl; p is 1-5; A is a radical, The radical is selected from phenyl, benzothiophenyl, pyridyl, pyrazinyl, benzofuranyl, benzimidazolyl, or indolyl; L ³ is absent, — (CH ₂ ) _0-1 N (R ³ ) C (═O) N ^{(R 3) -, - N} (R 3) C (= O) N (R 3) (CH 2) 0~1 -, - (CH 2) 0~1 N (R 3) C (= O) - , —N (R ³ ) C (═O) (CH ₂ ) _0-1 —, — (CH ₂ ) _0-1 SO ₂ N (R ³ ) —, —SO ₂ N (R ³ ) (CH ₂ ) _{^{0~1 -, - C (= NR}} 5) N (R 3) -, - C (= NR 5) _{^{-, - (CH 2) 0~1}} N (R 3) CO 2 -, - N (R 3) CO 2 (CH 2) 0~1 -, - C (= O) -, - CO 2 -, - (CH ₂ ) _{0 to 1} N (R ³ ) C (═NR ⁵ ) N (R ³ ) — or — (CH ₂ ) _{0 to 1} N (R ³ ) — is selected.

In another example, the compound is in accordance with International Publication No. [0056], wherein when A is phenyl, L ³ is —N (R ³ ) C (═O) N (R ³ ) —. is there.

  In another example, the compound is in accordance with International Publication No. [0057], where A is either phenyl or benzimidazolyl.

  In another example, the compound is either Formula VIIa or Formula VIIb, according to International Publication No. [0058]

Here, R ¹ is —H, halogen, haloalkyl, haloalkoxy, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —CO. ₂ R ³ , —C (═O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —NCO ₂ R ³ , —C (═O) R ³ , optionally substituted alkoxy, optionally substituted heterocyclyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, or Optionally selected from substituted cycloalkyl; m is 1-5; R ² is —H, halogen, haloalkyl, —CN, —NO ₂ , —OR ³ , —N (R ³ ); Selected from R ³ , or optionally substituted lower alkyl R ⁶ is —H, halogen, haloalkyl, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —N (R ³ ) C; (═O) C (═O) N (R ³ ) R ³ , —CO ₂ R ³ , —C (═O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —NCO ₂ R ³ , —C (═O) R ³ , optionally substituted alkoxy, optionally substituted heterocyclyl, or optionally substituted lower Selected from alkyl; p is 1-5.

  In another example, the compound is according to International Publication No. [0059], wherein the phenylurea in VIIb is in either the meta or para position relative to the pyrazole moiety.

  In another example, the compound is either Formula VIIc or Formula VIId according to WO [0060]

Here, R ¹ is —H, halogen, haloalkyl, haloalkoxy, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —CO. ₂ R ³ , —C (═O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —NCO ₂ R ³ , —C (═O) R ³ , optionally substituted alkoxy, optionally substituted heterocyclyl, or optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, Or optionally selected from optionally substituted cycloalkyl; R ^3a and R ^3b are each independently selected from —H or optionally substituted lower alkyl; optionally, R ^3a and R ^{3 nitrogen. 3b,} to which they are attached Together, combined, heteroalicyclyl be formed which is optionally substituted, said heteroalicyclyl is one and containing additional hetero atoms between two; is R ^6, -H, halogen , _{^{haloalkyl, -CN, -NO 2, -OR 3}} , -N (R 3) R 3, -S (O) 0~2 R 3, -N (R 3) C (= O) C (= O) N (R ³ ) R ³ , —CO ₂ R ³ , —C (═O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —NCO ₂ R ³ , —C (═O) R ³ , optionally substituted alkoxy, optionally substituted heterocyclyl, or optionally substituted lower alkyl; p is 1-5.

In another example, the compound is in accordance with International Publication No. [0061], wherein for VIIc, —N (R ^3a ) R ^3b is either in the meta or para position relative to the pyrazole moiety. And the phenylurea in VIId is in either the meta or para position relative to the pyrazole moiety.

  In another example, the compound is selected from Table 1 according to International Patent Publication Paragraph [0023].

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  Another aspect of the present invention is a pharmaceutical composition comprising a compound according to any one of International Publication Nos. [0023] to [0063] and a pharmaceutically acceptable carrier.

  Another aspect of the present invention is a metabolite of a compound or pharmaceutical composition according to any one of International Publication Nos. [0023] to [0064].

  Another aspect of the invention is a method of modulating the in vivo activity of a kinase, the method comprising administering to a subject an effective amount of the composition, the composition comprising: [0023] A compound according to any one of [0023] to [0063] and at least one pharmaceutical composition according to paragraph [0064] of the international publication.

  Another aspect of the present invention is a method according to International Publication No. [0066], wherein the kinase is selected from c-Kit and flt-3.

  Another aspect of the invention is a method according to WO [0067], wherein the step of modulating the in vivo activity of said kinase comprises inhibition of said kinase.

  Another aspect of the present invention is a method of treating a disease or disorder associated with uncontrollable abnormalities and / or unwanted cellular activity, said method comprising a therapeutic efficacy of the composition in a mammal in need thereof. Comprising the step of administering an amount, wherein the composition comprises at least one of a compound according to any one of the international publication paragraphs [0023] to [0063] and a pharmaceutical composition according to the international publication paragraph [0064]. Contains seeds.

  Another aspect of the present invention is a method for screening for a modulator of a kinase, comprising a compound according to any one of International Patent Publications [0023] to [0063] and a pharmaceutical according to International Publication [Paragraph [0064]. Combining at least one of the compositions with any of the at least one candidate reagent and determining the effect of the candidate reagent on the activity of the kinase.

  Another aspect of the present invention is a method for inhibiting proliferation activity in a cell, wherein the compound according to any one of International Publication Nos. [0023] to [0063] and the international publication are applied to the cell or the plurality of cells. Administering at least one effective amount of a pharmaceutical composition according to publication paragraph [0064].

(Definition)
As used herein, the following terms and phrases generally include the following unless the context in which they are used explicitly expresses otherwise or indicates something different: It is interpreted to have the meaning described in.

  The symbol “-” means a single bond, “=” means a double bond, and “≡” means a triple bond. symbol

Means a group on the double bond so as to occupy any position at the end of the double bond to which the symbol is attached; that is, the relative position E- or Z- of the double bond is ambiguous . When double bonds are depicted in text form (eg, -C (H) = C (H)-), this means describing both E-relative and Z-relative positions. When a group is depicted being removed from its parent formula,

The symbol is used at the end of a bond that is theoretically cleaved to separate the group from its parent structure.

A chemical formula uses a descriptor such as “R ¹ ”, which involves a list of formulas or words that describe the scope of what the descriptor means. Subsequent descriptors such as “R ^1a ” are used to describe a subset of the range of R ¹ , and “R ^1b ” is used to describe another subset of the range of R ^1. Etc. In such a continuous case, all other expressions involving simply “R ¹ ” are meant to include the entire range of this descriptor.

When chemical structures are depicted or described, unless otherwise stated, all carbons are assumed to have hydrogen substitutions in order to fit the four valences. For example, the structure on the left side of the schematic below contains 9 hydrogens. These nine hydrogens are depicted in the structure on the right. Sometimes certain atoms in the structure are described as such, with hydrogen (expressly defined hydrogen) as a substituent (eg, —CH ₂ CH ₂ —). It will be appreciated by those skilled in the art that the delineation techniques are common to simplify and simplify the delineation of complex structures.

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  In the present application, some structures are generally depicted and described as such. For example, in the scheme below, in the left-hand structure, ring A is used to describe “spirocyclyl” and if ring A is cyclopropyl, ring A contains no more than 4 Hydrogen is present (where “R” can also be —H). In another example, as depicted on the right side of the following scheme, if ring B is used to describe “phenylene”, ring B may have at most 4 hydrogens. (Assuming the depicted cleaved bond is not a C—H bond).

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  If the “R” group is depicted as “floating” in the ring system, for example:

Unless otherwise specified, the substituent “R” is assumed to replace the depicted hydrogen, implied hydrogen, or explicitly defined hydrogen from one of those ring atoms, so long as a stable structure is formed. And can be present on any atom of the ring system.

  If the “R” group is depicted as floating in a fused ring system, for example:

Unless otherwise indicated, the substituent “R” may be drawn from one of its ring atoms to the depicted hydrogen (eg, —NH— in the above formula), implied hydrogen (as long as a stable structure is formed). For example, as in the above formula, hydrogen is not shown but is understood to be present) or explicitly defined hydrogen (eg, where “X” is Can be present on any atom of the fused ring system. In the depicted example, the “R” group can be present on either the 5-membered or 6-membered ring of the fused ring system. In the formula depicted above, for example, when y is 2, two “R” again assume that each replaces the depicted hydrogen, implied hydrogen or explicitly defined hydrogen on the ring. And can be on any two atoms on the ring system.

  When a “R” group is depicted as being present in a ring system containing a saturated carbon, for example as in the formula:

(Here, in this example, “y” can be greater than 1 assuming that it replaces the currently depicted hydrogen, the implied hydrogen or the explicitly defined hydrogen, each of which is cyclic), in particular Unless stated otherwise, two “R” s may be on the same carbon if the resulting structure is stable. A simple example is when R is a methyl group; in the depicted ring carbon, there may be zwitter dimethyl ("cyclic" carbon). In other examples, two Rs on the same carbon may include that carbon to form a ring, and thus, for example, together with the depicted ring, as in the following formula, a spiro ring ("spirocyclyl" Base) make structure:

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“Alkyl” is understood to include (inclusive) linear, branched, or cyclic hydrocarbon structures and combinations thereof. For example, “C ₈ alkyl” may mean n-octyl, isooctyl, cyclohexylethyl, and the like. Lower alkyl means an alkyl group having 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like. Higher alkyl means an alkyl group containing more than 8 carbon atoms. Representative alkyl groups are those of C _{20 or} below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups having from 3 to 13 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like. As used herein, alkyl means alkanyl, alkenyl and alkynyl residues (and combinations thereof); it is taken to include cyclohexylmethyl, vinyl, allyl, isoprenyl and the like. Thus, when naming an alkyl residue having a certain number of carbons, it is interpreted to include all geometric isomers having that number of carbons; thus, for example, “butyl” or “C ₄ alkyl” either ", n- butyl, sec- butyl, isobutyl, t- butyl is meant to include isobutenyl and but-2-yn radical; and, for example," propyl "or" _{C 3} alkyl " Each includes n-propyl, propenyl and isopropyl. Otherwise, in the specific definition of a group, if alkenyl and / or alkynyl descriptors are used (eg, “C ₄ alkenyl” together with “C ₄ alkyl”), then the geometric isomer of C ₄ alkenyl is Other 4 carbon isomers are not meant to include “C ₄ alkyl”, for example, C ₄ alkynyl. For example, a more general description may describe specific groups such as “C _1-8 alkyl”, with the intention of encompassing the invention as a whole, whereas preferred species are “C _{1- The} same groups may be described, including “ ₈ alkyl”, “C _1-6 alkenyl” and “C _1-5 alkynyl”.

“Alkylene” means a straight or branched divalent radical consisting solely of carbon and hydrogen atoms, which is free of unsaturation and has 1 to 10 carbon atoms (eg, Methylene, ethylene, propylene, n-butylene, etc.). Alkylene is a subset of alkyl and means the same residue as alkyl except that it has two points of attachment and is specifically fully saturated. Examples of alkylene include ethylene (—CH ₂ CH ₂ —), propylene (—CH ₂ CH ₂ CH ₂ —), dimethyl propylene (—CH ₂ C (CH ₃ ) ₂ CH ₂ —) and cyclohexyl propylene (—CH ₂ CH ₂ CH (C ₆ H ₁₃ )).

  “Alkylidene” means a straight or branched unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from 2 to 10 carbon atoms (eg, ethylidene, propylidene, n -Butylidene). Alkylidene is a subset of alkyl and means the same residue as alkyl except that it has two points of attachment and specifically double bond unsaturation. The unsaturation present includes at least one double bond.

  “Alkylidin” means a straight or branched unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having 2 to 10 carbon atoms (eg, propyl-2-ynyl). N-butylide-1-ynyl, etc.). Alkylidin is a subset of alkyl and means the same residue as alkyl except that it has two points of attachment and specifically a triple bond. The unsaturation present includes at least one triple bond.

  Any of the above radicals “alkylene”, “alkylidene” and “alkylidyne”, when optionally substituted, may contain alkyl substitution, including unsaturation per se. For example, 2- (2-phenylethynyl-but-3-enyl) -naphthalene (IUPAC name) contains an n-butylid-3-ynyl radical with a vinyl substituent at the 2-position of the radical.

  “Alkoxy” or “alkoxyl” refers to an —O-alkyl group, which is one of linear, branched, cyclic, unsaturated, and combinations thereof attached to the parent structure through an oxygen atom, for example. Means 8 to 8 carbon atoms). Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower alkoxy means a group containing 1 to 6 carbons.

“Substituted alkoxy” refers to the group —O- (substituted alkyl) wherein substituents on the alkyl group generally include those other than carbon (as defined for alkoxy). Exemplary substituted alkoxy groups include “polyalkoxy”, ie, —O—optionally substituted alkylene—optionally substituted alkoxy (eg, —OCH ₂ CH ₂ OCH ₃ ) and glycol ethers (eg, Polyethylene glycol and —O (CH ₂ CH ₂ O) _x CH ₃ , where x is an integer between about 2 and about 20, in other examples an integer between about 2 and about 10, Yet another example is an integer between about 2 and about 5.) Other representative substituted alkoxy groups include hydroxyalkoxy, ie, —OCH ₂ (CH ₂ ) _y OH, where y is an integer between about 1 and about 10, for example, in other examples , Y is an integer between about 1 and about 4.

  “Acyl” means a group having 1-10 carbon atoms of straight chain, branched, cyclic configuration, unsaturated chain, and combinations thereof attached to the parent structure through a carbonyl function. One or more carbons in the acyl residue can be replaced with nitrogen, oxygen or sulfur as long as the point of attachment to the parent moiety remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower acyl means a group containing 1 to 6 carbons.

  “Α-amino acid” means naturally occurring amino acids and commercially available amino acids and optical isomers thereof. Typical natural and commercially available α-amino acids include glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, omithine, histidine, arginine, cysteine, There are homocysteine, methionine, phenylalanine, homophenylalanine, phenylglycine, orthotyrosine, metatyrosine, paratyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline. “The side chain of an α-amino acid” means a radical (for example, hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine), etc.) present on the carbon of the α-amino acid defined above. means.

“Amino” refers to the group —NH ₂ . “Substituted amino” refers to the group —N (H) R or —N (R) R, wherein each R is independently selected from the group consisting of: optionally substituted. Alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, acyl, carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl (eg, diethylamino, methylsulfonylamino and furanyl-oxy) -Sulfonamino).

  “Aryl” means a 6- to 14-membered cyclic carbon (for example, a monovalent radical such as benzene, naphthalene, indane, tetralin, fluorene, etc.). As monovalent radicals, examples of said rings include phenyl, naphthyl, indanyl, tetranylyl and fluorenyl.

  “Arylene” generally refers to any aryl having at least two non-hydrogen groups attached thereto. As a more specific example, “phenylene” refers to a divalent phenyl ring radical. Phenylene can therefore be bound by more than two groups, but is defined by having at least two non-hydrogen groups bound thereto. The term “ortho-arylene”, “meta-arylene” or “para-arylene” means a geometric isomer of a particular arylene, where two groups attached to the aryl as depicted in the formula. Are each placed in an ortho, meta or para geometric relationship with respect to aryl.

“Arylalkyl” means a residue in which an aryl moiety is attached to the parent structure through one of an alkylene, alkylidene, or alkylidyne radical. Examples include benzyl, phenethyl, phenyl vinyl, phenyl allyl and the like. Both the aryl of the arylalkyl group and the corresponding alkylene, alkylidene, or alkylidine radical moiety can be optionally substituted. “Lower arylalkyl” means an arylalkyl in which the “alkyl” portion has 1 to 6 carbons; this can also be referred to as _{arylC 1-6} alkyl.

  “Exo-alkenyl” means a double bond emanating from a ring and not within a ring system; for example, the double bond is depicted by the following formula:

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  In some instances, as those skilled in the art will appreciate, two adjacent groups in an aromatic system can be fused together to form a ring structure. The fused ring structure can contain heteroatoms and can be optionally substituted with one or more groups. Furthermore, it should be noted that the saturated carbon of such fused groups (ie, saturated ring structures) can contain two substituents.

  “Fused-polycyclic” or “fused ring system” means a polycyclic ring system containing a bridged ring or fused ring; that is, where two rings are within their structure Has more than one shared atom. In the present application, fused-polycyclic compounds and fused ring systems are not necessarily all aromatic ring systems. Typically, although not necessarily, fused-polycyclic compounds share a close set of atoms (eg, naphthalene or 1,2,3,4-tetrahydro-naphthalene). A spiro ring system is not a fused-polycyclic compound in this definition, but the fused polycyclic ring system of the present invention itself has a spiro ring via a single ring atom of the fused-polycyclic compound. You can join there.

  “Halogen” or “halo” means fluorine, chlorine, bromine or iodine. “Haloalkyl” and “haloaryl” generally refer to alkyl and aryl radicals substituted with one or more halogens, respectively. Thus, “dihaloaryl”, “dihaloalkyl”, “trihaloaryl” and the like mean aryl and alkyl substituted with multiple halogens, but not necessarily multiple identical halogens; -Chloro-3-fluorophenyl falls within the scope of dihaloaryl.

  “Heteroarylene” generally refers to a bicameral heteroaryl having at least two groups attached thereto. As a more specific example, “pyridylene” refers to a divalent pyridyl ring radical. A pyridylene is therefore defined by the fact that more than two groups can be attached, but at least two non-hydrogen groups are attached thereto. For purposes of this application, the term “ortho-heteroarylene” refers to a particular heteroarylene geometric isomer, wherein the two groups attached to the heteroaryl as depicted in the formula are: Located on the adjacent atom of the heteroaryl.

  “Hetero atom” means O, S, N or P.

“Heterocyclyl” means a stable 3- to 5-membered ring radical consisting of carbon atoms and 1 to 5 heteroatoms, which includes nitrogen, phosphorus, oxygen and sulfur. Selected from the group consisting of For the purposes of the present invention, a heterocyclyl radical can be a monocyclic, bicyclic or tricyclic ring system, which can include not only fused or bridged ring systems, but also spirocyclic ring systems; Nitrogen, phosphorus, oxygen and sulfur atoms within the heterocyclyl radical can be oxidized to various oxidation states as desired. In particular examples, the —S (O) _0-2- group refers to —S— (sulfide), —S (O) — (sulfoxide) and —SO ₂ — (sulfone). For convenience, nitrogen (especially, but not limited to, defined as cyclic aromatic nitrogen) is meant to include their corresponding N-oxide forms, but in certain instances, such obvious Is not defined. Thus, for example, for a compound of the invention having a pyridyl ring; the corresponding pyridyl-N-oxide is meant to include other compounds of the invention. In addition, the cyclic nitrogen atom can be quaternized if desired; the ring radical can be partially or fully saturated or aromatic. Examples of heterocyclyl radicals include azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, Purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridy , Tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl Isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzopyrazolyl, benzoimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl , Benzothieryl, thiamorpholinyl, thiamorpholinyls Sulfoxide, thiamorpholinyl sulfone, although dioxaphospholanyl and oxadiazolyl include, but are not limited to.

  “Heteroalicyclic” specifically means a non-aromatic heterocyclyl radical. Heteroalicyclics can contain unsaturation but are not aromatic.

  “Heteroaryl” refers specifically to an aromatic heterocyclyl radical.

“Heterocyclylalkyl” means a residue in which a heterocyclyl is attached to a parent structure via an alkylene, alkylidene, or alkylidyne radical. Examples include (4-methylpiperazin-1-yl) methyl, (morpholin-4-yl) methyl, (pyridin-4-yl) methyl, 2- (oxazolin-2-yl) ethyl, 4- (4- Methylpiperazin-1-yl) -2-butenyl and the like. Both the heterocyclyl of the heterocyclylalkyl group and the corresponding alkylene, alkylidene, or alkylidyne radical moiety can be optionally substituted. “Lower heterocyclylalkyl” means a heterocyclylalkyl in which the “alkyl” portion of the group has one to six carbons. “Heteroalicyclic alkyl” specifically means a heterocyclylalkyl in which the heterocyclyl portion of the group is non-aromatic; and “heteroarylalkyl” means that the heterocyclyl portion of the group is aromatic. It means a certain heterocyclylalkyl. Such terms may be described in more than one manner, for example, “lower heterocyclylalkyl” and “heterocyclylC _1-6 alkyl” are equivalent terms.

“Arbitrary” or “as required” means that the event or situation described subsequently may or may not occur, and that this description may or may not occur. It means to include. The skilled person means that only any compound that is sterically feasible and / or synthetically feasible with respect to what any molecule is described as containing one or more optional substituents. Understand what to do. “Optionally substituted” means all subsequent modifiers within the term, eg, “optionally substituted aryl C _1-8 alkyl” where any substitution is defined as _Can occur in both “C _1-8 alkyl” and “aryl” moieties; for example, optionally substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are optionally substituted Defined as containing substituted alkyl groups and may continue indefinitely. A list of representative optional substituents is included below in the definition of “substituted”.

  “Saturated bridged ring system” means a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but may not contain aromatic or heteroaromatic rings in its core structure (although it may have aromatic substitution). For example, hexahydro-furo [3,2-b] furan, 2,3,3a, 4,7,7a-hexahydro-1H-indene, 7-aza-bicyclo [2.2.1] heptane and 1,2, 3,4,4a, 5,8,8a-Octahydro-naphthalene are all included in the “saturated bridged ring system” class.

  “Spirocyclyl” or “spirocyclic ring” means a ring made from the cyclic carbon of another ring. For example, as depicted below, the ring atoms (but not the bridgehead atoms) of the saturated bridged ring system (rings B and B ′) are linked to the saturated bridged ring system and the spirocyclyl (ring A) attached thereto. It can be an atom shared between them. Spirocyclyl can be carbocyclic or heteroalicyclic.

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“Substituted” alkyl, aryl, and heterocyclyl, respectively, are alkyl, aryl, and heterocyclyl in which one or more (eg, up to about 5, in other examples, up to about 3) hydrogen atoms are replaced with substituents. Wherein the substituents are independently selected from: optionally substituted alkyl (eg, fluoromethyl, hydroxypropyl, nitromethyl, aminoethyl, etc.), optionally substituted aryl (eg, , 4-hydroxyphenyl, 2,3-difluorophenyl, etc.), optionally substituted arylalkyl (eg, 1-phenyl-ethyl, para-methoxyphenylethyl, etc.), optionally substituted heterocyclylalkyl (eg, 1-pyridin-3-yl-ethyl, N-ethylmorpholino, etc.), Optionally substituted heterocyclyl (eg, 5-chloro-pyridin-3-yl, 1-methyl-piperidin-4-yl, etc.), optionally substituted alkoxy (eg, methoxyethoxy, hydroxypropyloxy, methylene) Dioxy, etc.), optionally substituted amino (eg, methylamino, diethylamino, trifluoroacetylamino, etc.), optionally substituted amidino, optionally substituted aryloxy (eg, phenoxy, para- Chlorophenoxy, meta-aminophenoxy, para-phenoxyphenoxy, etc.), optionally substituted arylalkyloxy (eg, benzyloxy, 3-chlorobenzyloxy, meta-phenoxybenzyloxy, etc.), carboxy (—CO ₂ H ), Replace if necessary Carboalkoxy (ie acyloxy or —OC (═O) R), optionally substituted carboxyalkyl (ie ester or —CO ₂ R), optionally substituted carboxamide, optionally substituted Benzyloxycarbonylamino (CBZ-amino), cyano, optionally substituted acyl, halogen, hydroxy, nitro, optionally substituted alkylsulfanyl, optionally substituted alkylsulfinyl, optionally substituted Alkylsulfonyl, thiol, oxo, carbamyl, optionally substituted acylamino, optionally substituted hydrazino, optionally substituted hydroxylamino, and optionally substituted sulfonamide.

  “Sulfanyl” refers to the following groups: —S— (optionally substituted alkyl), —S— (optionally substituted aryl), and —S— (optionally substituted). Heterocyclyl).

  “Sulfinyl” means the following groups: —S (O) —H, —S (O) — (optionally substituted alkyl), —S (O) —optionally substituted aryl. ), And -S (O)-(optionally substituted heterocyclyl).

"Sulfonyl" refers to the _{groups: -S (O 2) -H,} -S (O 2) - ( alkyl optionally _{substituted), - S (O 2)} - optionally Substituted aryl), —S (O ₂ ) — (optionally substituted heterocyclyl), —S (O ₂ ) — (optionally substituted alkoxy), —S (O ₂ ) —optional. Substituted aryloxy), and —S (O ₂ ) — (optionally substituted heterocyclyloxy).

  “Yield” for each of the reactions described herein is expressed as a percentage of the theoretical yield.

  Some of the compounds of the present invention may have imino, amino, oxo or hydroxy substituents away from the aromatic heterocyclyl system. For the purposes of this disclosure, it is understood that such imino, amino, oxo or hydroxy substituents can exist in their corresponding tautomeric forms (ie, amino, imino, hydroxy or oxo, respectively). .

  The compounds of the present invention are named according to the International Union of Pure and Applied Chemistry (IUPAC), the International Union of Biochemistry and the Molecular Biology (IUBMB), and the Chemistry's nomenclature. Named.

  Tautomer. As is known to those skilled in the art, the compounds can exist in tautomeric forms. Of particular relevance to the present invention are possible tautomeric forms of, for example, pyrazole, benzimidazole and 1,3-diketone. A representative depiction of pyrazole tautomerism is shown below.

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  In this application, compounds may be depicted in a particular tautomeric form for purposes of illustration, however, such illustrations are meant to include all tautomeric forms. Note: The tautomeric form in which a compound is depicted also determines, for example, the IUPAC name for that compound. As explained above, tautomers A and B have different IUPAC names (other naming schemes can give different names for a particular tautomer). In the IUPAC system, tautomer A is N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-[4- (5-phenyl-1H-pyrazol-3-yl) phenyl] urea. And tautomer B is N- [4-chloro-3- (trifluoro-methyl) phenyl] -N ′-[4- (3-phenyl-1H-pyrazol-5-yl) phenyl]. Urea. Those skilled in the art will understand that these names (and tautomeric designations) refer to the same compound.

  The tautomer / name problem is seemingly complicated when different parts of the molecule each have possible tautomers. For example, the compounds described below (the compounds of the invention) have four different tautomeric forms, each with a corresponding unique IUPAC name. This compound depends on how the tautomers of its pyrazole and benzimidazole moieties are depicted, N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-( 4- {5- [6- (4-Methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-3-yl} phenyl) urea, N- [4-chloro-3- (Trifluoromethyl) phenyl] -N ′-(4- {5- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-3-yl} phenyl ) Urea, N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [6- (4-methyl-piperazin-1-yl) -1H-benzimidazole-2 -Il] -1 -Pyrazol-5-yl} phenyl) urea or N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) urea. Therefore, in this description, illustrations and names of specific tautomers are used for convenience. Such illustrations and names are meant to include all tautomeric forms of the particular molecule displayed.

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  The compounds of the present invention, or pharmaceutically acceptable salts thereof, may have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure.

  The compounds of the invention and their pharmaceutically acceptable salts can exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. These compounds can also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of the present invention.

  For the purposes of constructing a compound, it is assumed that such a configuration creates a stable structure when considering the general description of the compounds of the present invention. That is, one of ordinary skill in the art recognizes that there can theoretically exist several configurations that are not normally considered stable compounds (ie, sterically feasible and / or synthetically feasible (above)).

When a particular group having that binding structure is designated to bind to two partners; that is, a divalent radical (eg, —OCH ₂ —), unless otherwise specified, of these two partners It can be seen that either can be bound at one end to a particular group and the other partner is necessarily bound to the other end of this particular group. In other words, divalent radicals are not to be construed as limited to the depicted orientation, for example, “—OCH ₂ —” includes not only the depicted “—OCH ₂ —” but also “—CH ₂ O”. -"Also means.

  Methods for preparing and / or separating and isolating single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)-and (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) can be resolved by methods known to those skilled in the art, for example, by: formation of diastereomeric salts or complexes that can be separated by crystallization; for example, crystals Formation of diastereomeric derivatives that can be separated by isomerization, selective reaction of one enantiomer with an enantiomer specific reagent (eg, enzymatic oxidation or reduction), followed by denatured and non-denatured enantiomers Or gas-liquid or liquid chromatography in a chiral environment, such as a chiral support (eg, silica with a chiral ligand attached or in the presence of a chiral solvent). It can be appreciated that when the above separation procedure converts the desired enantiomer into other chemical elements, additional steps may be required to liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting enantiomers to others by asymmetric transformations. For a mixture of enantiomers enriched in a particular enantiomer, the main component enantiomer can be further enriched (with concomitant loss in yield) by recrystallization.

  “Patient” for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus, the method is applicable for both human therapy and veterinary applications. In a preferred embodiment, the patient is a mammal, and in the most preferred embodiment, the patient is a human.

  “Kinase-dependent diseases or conditions” refer to pathological conditions that depend on the activity of one or more protein kinases. Kinases are directly or indirectly involved in signal transduction pathways of various cellular activities, including proliferation, adhesion, migration, differentiation and invasion. Diseases associated with kinase activity include diseases associated with tumor growth, pathological neovascularization that supports solid tumor growth, and other diseases associated with excessive local angiogenesis (eg, diseases of the eyeball (diabetic) Retinopathy, age-related macular degeneration, etc.) and inflammation (psoriasis, rheumatoid arthritis, etc.)).

  Although not wishing to become theoretical, phosphatases also serve as kinases' cognate in “kinase-dependent diseases or conditions”; that is, for example, protein kinases, kinases phosphorylate, and Phosphatase dephosphorylates. Thus, as described herein, compounds of the present invention modulate kinase activity, while phosphatase activity may also be modulated directly or indirectly. This further modulation, if present, is synergistic (or not) with respect to the activity of the compound of the invention with respect to the relevant kinase or kinase family or otherwise with respect to the interdependent kinase or kinase family. Synergistic). In any event, as noted above, the compounds of the present invention provide abnormal levels of cellular proliferation (ie, tumor growth), programmed cell death (apoptosis), cell migration, and invasion and angiogenesis associated with tumor growth. Useful for treating diseases characterized in part by formation.

  A “therapeutically effective amount” is the amount of a compound of the invention that, when administered to a patient, ameliorates the symptoms of the disease. The amount of a compound of the invention that constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and severity of the disease, the age of the patient being treated, and the like. The therapeutically effective amount can be routinely determined by one of ordinary skill in the art in view of his knowledge and the present disclosure.

  “Cancer” refers to a cell proliferative disease state, including but not limited to: Cardiac: Sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma , Rhabdomyomas, fibromas, lipomas and teratomas; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) carcinoma, bronchial adenoma , Sarcoma, lymphoma, chondromatomatous hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma) ), Pancreas (ductal adenocarcinoma), insulinona, glucagonoma, gastrinoma, carcinoma, bipoma), small intestine (adenocarcinoma, lymphoma, carcinoma) , Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilmsoma) [Nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratomas, embryonic carcinoma, Teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, germoma, hemangiosarcoma, hepatocellular adenoma, blood vessel Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell chordoma (malignant) giant cell tumor chordoma), osteochondroma (osteochondroma extraossematosis), benign cartilage species, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; nervous system: cranium (osteoma, hemangioma) , Granulomas, xanthomas, osteotis defonians, meninges (meningiomas, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma) Tumor, ependymoma, germinoma [pineomas], pleomorphic glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibromas, meningiomas, Gynecological: uterus (endometrial carcinoma), cervical carcinoma (cervical carcinoma), pre-tumor cervical dysplasia), ovary (ovarian carcinoma [serous cyst gland) Cancer, whip Cystadenocarcinoma, unclassified carcinoma], granulosa cell-envelope cell tumor, Sertoli-Leydig cell tumor, anaplastic germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepidermal carcinoma) , Adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, grape sarcoma (fetal rhabdomyosarcoma), fallopian tube (carcinoma); blood: blood (myeloid leukemia [acute And chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome), Hodgkin disease, non-Hodgkin lymphoma [malignant lymphoma]; skin: malignant melanoma, basal Cell carcinoma, squamous cell carcinoma, Kaposi sarcoma, mole dysplastic nevi, lipoma, hemangioma, dermal fibroma, keloid, psoriasis; And adrenal gland: neuroblastoma. Accordingly, as provided herein, the term “cancer (sex) cell” includes cells affected by any one of the above noted conditions.

  “Pharmaceutically acceptable acid addition salts” refers to salts that retain the biological effectiveness of the free base, and they are not biologically or otherwise undesirable and include inorganic acids ( Eg, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (eg, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid) , Fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

  “Pharmaceutically acceptable base addition salts” include inorganic bases (eg, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum) Salt). Typical salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary amine salts, secondary amine salts, as well as tertiary amine salts, substituted amines (including naturally occurring substituted amines). ) Salts, cyclic amine salts and basic ion exchange resin salts (eg, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine) Arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethi Piperazine, polyamine resins), include, but are not limited to. Representative organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine (see, eg, SM Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977). 66: 1-19, which is incorporated herein by reference).

  “Prodrug” refers to a compound that has been transformed (typically rapidly) in vivo (eg, hydrolyzed in the blood) to obtain the parent compound of the formulation. Common examples include, but are not limited to, ester forms and amide forms of compounds having an active form that produces a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the invention include alkyl esters (eg, having between about 1 and about 6 carbons), where the alkyl group can be linear or branched. A branched chain), but is not limited thereto. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to, benzyl. Examples of pharmaceutically acceptable amides of the compounds of the invention include primary amides, secondary alkyl amides, and tertiary alkyl amides (eg, between about 1 and about 6 carbons). (But not limited to). Amides and esters of the compounds of the present invention may be prepared according to conventional methods. For a discussion of prodrugs, see T.W. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” A.A. C. S. Symposium Series, Volume 14, and Bioreversible Carriers in Drug Design, Editor Edward B. Provided in Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference for all purposes.

  “Metabolite” refers to a break-down product or end product of a compound or salt thereof produced by metabolism or biotransformation in the animal or human body; for example (eg, by oxidation) Biotransformation to more polar molecules, by reduction, or hydrolysis, or biotransformation to conjugates (for a discussion of biotransformation, see Goodman and Gilman, “The Pharmaceutical Basis of Therapeutics”. (See 8th Addendum, Pergamon Press, Gilman et al. (Ed.), 1990). As used herein, a metabolite of a compound of the present invention or a salt thereof may be a biologically active form of the compound in the body. In one example, a prodrug can be used such that its biologically active form (metabolite) is released in vivo. In another example, biologically active metabolites are unexpectedly discovered. That is, it does not design its own prodrug. Assays for metabolite activity of the compounds of the present invention are known to those of skill in the art in light of the present disclosure.

  Furthermore, the compounds of the present invention can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, for the purposes of the present invention, the solvated forms are considered equivalent to the unsolvated forms.

  Furthermore, the present invention is made either using standard organic synthesis techniques (including combinatorial chemistry) or by biological methods (eg, bacterial digestion, metabolism, enzymatic conversion, etc.). It is intended to cover the compound.

  As used herein, “treating” or “treatment” covers treatment of a disease state in humans, which includes abnormal cell proliferation and abnormal cell invasion. And includes at least one of the following: (i) preventing the development of a disease state in a human, in particular, such a human is afflicted with the disease state. Easy (but not yet diagnosed as a disease state); (ii) inhibiting the disease state (ie, preventing its development); and (iii) reducing the disease state (ie, Causing regression of the above disease states). As is known in the art, adjustments regarding systemic versus local delivery, age, weight, overall body health, sex, diet, time of administration, drug interactions and severity of condition may be necessary, and Confirmed by a person skilled in the art through routine experimentation.

  Those skilled in the art will recognize that certain crystallized protein-ligand complexes (especially c-Kit and flt-3 ligand complexes) and their corresponding X-ray structure coordinates are described herein. It is understood that it can be used to reveal new structural information useful for understanding the biological activity of kinases as described in. Similarly, important structural features of the above-mentioned proteins (especially the shape of the ligand binding site) are useful in methods for the design or identification of selective modulators of kinases, and others with similar features. This is useful in elucidating protein structures. Such protein-ligand complexes (with the compounds of the invention as their ligand component) are an aspect of the invention.

  Similarly, those skilled in the art will appreciate that such appropriate x-ray quality crystals can be used as part of a method for identifying candidate factors that can bind and modulate the activity of a kinase. . Such a method may be characterized by the following aspects: a) an aspect that is introduced into an appropriate computer program, an aspect that introduces information defining a ligand binding domain of a kinase in a conformation (eg, as described above) When defined by X-ray structural coordinates obtained from appropriate X-ray characteristic crystals), wherein the computer program creates a model of the three-dimensional structure of the ligand binding domain, b) in the computer program An aspect of introducing a model of the three-dimensional structure of the candidate factor; c) an aspect of superimposing the candidate factor model on the model of the ligand binding domain; and d) the candidate factor model being a space with respect to the ligand binding domain. Aspect to evaluate whether it fits in. Aspects a) to d) are not necessarily performed in the order described above. Such a method may further involve an aspect of performing rational drug design using a model of a three-dimensional structure, and an aspect of selecting strong candidate factors in combination with computer modeling.

  Furthermore, those skilled in the art will appreciate that such methods may further require the following: determined in this way to spatially match the ligand binding domain in a biological activity assay for kinase regulation. Use of the candidate factor and measurement of whether this candidate factor modulates kinase activity in the assay. Such methods can also include administering a candidate agent determined to modulate kinase activity to a mammal suffering from a condition treatable by kinase modulation (eg, as described above).

  The skilled artisan will also understand that the compounds of the invention can be used in methods to assess the ability of a test agent to associate with a molecule or molecular complex (including the ligand binding domain of a kinase). Such a method may be characterized by the following aspects: a) the aspect of creating a computer model of the kinase binding pocket using structural coordinates obtained from the appropriate X-ray characteristic crystal method of the kinase, b) An aspect of using a computational algorithm to perform a fitting operation between the test factor and the computer model of the binding pocket; and c) between the test factor and the computer model of the binding pocket. An aspect of analyzing the result of the fitting operation to quantify the meeting.

(General administration)
Administration of the compounds of the invention, or pharmaceutically acceptable salts thereof, in pure form or in an appropriate pharmaceutical composition may be via any accepted mode of administration, or agent that provides similar utility. Can be done. Thus, administration can be, for example, oral, nasal, parenteral (intravenous, intramuscular, or subcutaneous), topical, transdermal, intravaginal, intravesical, intracisternal, or rectal, Solid dosage form, semi-solid dosage form, lyophilized powder dosage form, or liquid dosage form form (eg, tablets, suppositories, pills, soft elastic materials and hard gelatin capsules, powders, solutions, suspensions Or an aerosol, etc.), preferably a unit dosage form suitable for single administration of precise dosages.

  The composition comprises a conventional pharmaceutical carrier or excipient and a compound of the invention as an active agent, and may further comprise other pharmaceutical agents, pharmaceutical agents, pharmaceutical carriers, pharmaceutical adjuvants, etc. . The compositions of the invention can be used in combination with anti-cancer or other factors commonly administered to patients to treat cancer. Adjuvants include preservatives, wetting agents, suspending agents, sweeteners, flavoring agents, fragrances, emulsifiers, and formulations. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal factors (eg, paraben, chlorobutanol, phenol, sorbic acid, etc.). It may also be desirable to include isotonic factors (eg, sugars, sodium chloride, etc.). Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents that delay absorption such as aluminum monostearate and gelatin.

  If desired, the pharmaceutical compositions of the present invention may also contain minor amounts of auxiliaries (eg, wetting or emulsifying agents, pH buffering agents, antioxidants, etc. (eg, citric acid, sorbitan monolaurate, triethanolamine oleate). , Butylated hydroxytoluene and the like)).

  Compositions suitable for parenteral injection are for reconstitution into sterile, physiologically acceptable water or non-aqueous solutions, dispersions, suspensions or emulsifiers, and sterile injectable solutions or dispersions. Sterile powders can be included. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (eg olive oil) ), And injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

  One preferred route of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of severity of the disease state being treated.

  Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound contains at least one inert conventional excipient (or carrier) (eg, sodium citrate or dicalcium phosphate) or (a) a filler (filler). ) Or bulking agents (eg, starch, lactose, sucrose, glucose, mannitol, and silicic acid), (b) binders (eg, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, Sucrose and gum arabic), (c) humectants (eg glycerol), (d) disintegrants (eg agar, calcium carbonate, potato starch or tapioca starch, alginic acid, croscarmellose) Sodium complex silicate (complex s liquate) and sodium carbonate), (e) solution set retarder (eg paraffin), (f) absorption enhancer (eg quaternary ammonium compound), (g) wetting agent ( Examples include cetyl alcohol, and glycerol monostearate, magnesium stearate, etc.), (h) adsorbents (eg, kaolin and bentonite) and (i) scales (eg, talc, calcium stearate, Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof). In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

  Solid dosage forms as described above can be prepared with coatings and shells such as enteric coatings and others well known in the art. These can contain pacifying agents and can also be compositions that release the active compound in certain areas of the intestinal tract in a delayed fashion. Examples of embedded compositions that can be used are polymeric substrates and waxes. The active compound may also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, sugar honey, and elixirs. Such dosage forms can be any pharmaceutical form of, for example, a compound of the invention, or a pharmaceutically acceptable salt thereof, and a carrier (eg, water, saline, water-soluble glucose, glycerol, ethanol, etc.). Adjuvants; solubilizers and emulsifiers (examples include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide); oils (particularly, Cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil), fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan; or mixtures of these substrates, etc. Result, the solution or suspension is formed.

  In addition to the active compounds, the suspensions are made up of suspending agents (for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, Or a mixture of these substrates).

  Compositions for rectal administration are, for example, suppositories, which are a compound of the invention together with, for example, suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycols or suppository waxes. ). They are solid at room temperature, but are liquid at body temperature and, as a result, release the active compound therein while melting in the appropriate body cavity.

  Dosage forms for topical administration of the compounds of this invention include ointments, powders, sprays, and inhalants. The active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated to be within the scope of the present invention.

  In general, depending on the intended mode of administration, the pharmaceutically acceptable composition comprises from about 1% to about 99% by weight of a compound of the invention or a pharmaceutically acceptable salt thereof, and 99% by weight. % To 1% by weight of a suitable pharmaceutical excipient. In one example, the composition comprises between about 5% and about 75% by weight of a compound of the invention, or a pharmaceutically acceptable salt thereof, the remainder being a suitable pharmaceutical excipient. .

  Actual methods of preparation of such dosage forms are known or apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, 18th Edition, (Mack Publishing Company, Easton, Pa., 1990). checking ... The composition to be administered in each case contains a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease state according to the teachings of the invention. Including.

  The compounds of the present invention, or pharmaceutically acceptable salts thereof, can have various factors (activity of the particular compound used, metabolic stability and length of action of the compound, age, weight, overall body health, gender Doses that vary depending on the diet, diet, mode and timing of administration, rate of excretion, combination of drugs, severity of the particular disease state, and treatment being received by the host Is done. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 mg to about 1,000 mg per day. As an example, a normal human adult having a body weight of about 70 kg is dosed in the range of about 0.01 mg / kg to about 100 mg / kg of body weight per day. However, the particular dosage used can vary. For example, the dosage may depend on a number of factors, including the amount required by the patient, the severity of the condition being treated, and the pharmacological activity of the compound used. Determination of optimal dosages for a particular patient is well known to those skilled in the art.

(Usefulness of the compound of the present invention as a screening factor)
For example, to use a compound of the invention in a method of screening for a candidate agent that binds to c-Kit or flt-3 receptor kinase, the protein is bound to a support and the compound of the invention is added for the assay. Is done. Alternatively, the compound of the invention is bound to the support and a protein is added. Among the new binding agents that can be explored, candidate factor classifications include specific antibodies, non-natural binding factors identified in chemical library screening, peptide analogs, and the like. Of particular interest are screening assays for candidate factors that have low toxicity to human cells. A wide variety of assays can be used for this purpose. Such assays include labeled in vitro protein-protein binding assays, electrophoretic mobility change assays, immunological assays for protein binding, functional assays (such as phosphorylation assays) and the like.

  Measurement of the binding of the candidate factor to, for example, c-Kit or flt-3 protein can be performed in various ways. In one example, the candidate agent (a compound of the invention) is labeled, for example with a fluorescent or radioactive moiety, and binding is measured directly. For example, a compound of the invention wherein all or a portion of the c-Kit or flt-3 protein is attached to a solid support and a labeled agent (eg, at least one atom is replaced with a detectable isotope) ), Washing away excess reagent and determining how much label is present on the solid support. Various blocking and washing steps can be utilized as is well known in the art.

  As used herein, “labeled” means that the compound provides a detectable signal (eg, radioisotope, fluorescent tag, enzyme, antibody, particle (eg, magnetic particle), chemiluminescent tag, or specific Labeling directly or indirectly using a molecule that binds to the target. Examples of the molecule that specifically binds include a pair of molecules (for example, biotin and streptavidin, digoxin and anti-digoxin, etc.). With respect to a specific binding member, the complementary member is normally labeled with a molecule that provides detection according to the known procedures described above. The label can provide a detectable signal directly or indirectly.

In some embodiments, only one of the components is labeled. For example, a c-Kit or flt-3 protein can be labeled with ¹²⁵ I at the tyrosine position, or can be labeled with a fluorophore. Alternatively, more than one component can be labeled with different labels (eg, using ¹²⁵ I for proteins and using a fluorophore for candidate agents).

  The compounds of the invention can also be used as competitors for screening for additional drug candidates. As used herein, a “candidate bioactive factor” or “drug candidate” or grammatical synonym is any molecule for testing for biological activity (eg, protein, oligopeptide, small organic molecule, Saccharides, polynucleotides, etc.). They can directly or indirectly change the cell proliferation phenotype or the expression of cell proliferative sequences (including both nucleic acid and protein sequences). In other cases, changes in binding and / or activity of cell proliferative proteins are screened. Some embodiments exclude molecules already known to bind to a particular protein if the binding or activity of the protein is screened. Exemplary embodiments of the assays described herein include candidate factors that do not bind to the target protein in its endogenous native state, and are termed “exogenous” factors herein. . In one example, the exogenous factor further excludes antibodies to c-Kit or flt-3.

  Candidate factors can include a number of chemical classifications, however, typically they are organic molecules having a molecular weight greater than about 100 daltons and less than about 2,500 daltons. Candidate factors include functional groups necessary for structural interactions with proteins (especially hydrogen bonds and lipophilic bonds), and typically at least amine groups, carbonyl groups, hydroxyl groups, ether groups, or Contains a carboxyl group (eg, at least two of the above functional groups). The candidate factors often comprise cyclical carbon or heterocyclic structures and / or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate factors are also found in biomolecules, including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives thereof, structural analogs, or combinations thereof.

  Candidate factors are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, a number of means are available for random and direct synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides. Alternatively, libraries of natural compounds in the form of bacterial extracts, fungal extracts, plant extracts and animal extracts are available or readily made. Furthermore, natural or synthetically generated libraries and compounds are readily modified through conventional chemical, physical and biochemical means. Known pharmacological agents can be subjected to direct or random chemical modification (eg, acylation, alkylation, esterification, amidification to produce structural analogs).

  In one example, the binding of the candidate agent is determined through the use of a competitive binding assay. In this example, the competitor is a binding component (eg, antibody, peptide, binding partner, ligand, etc.) known to bind c-Kit or flt-3. Under certain circumstances, there may be a competitive binding between the candidate agent and the binding moiety, wherein the binding component is replaced with the candidate agent.

  In some embodiments, the candidate agent is labeled. This candidate factor or the competitor or both, if present, is first added to the c-Kit or flt-3 protein for a time sufficient to allow binding. Incubations may be performed at any temperature that facilitates optimal activity, typically between 4 ° C and 40 ° C.

  Incubation times are not only selected for optimal activity, but can also be optimized to facilitate rapid high throughput screening. Typically between 0.1 and 1 hour is sufficient. Excess reagent is generally removed or washed away. A second component is then added, indicating binding by following the presence or absence of the labeled component.

  In one example, the competitor is added first, followed by the candidate agent. Competitive replacement allows this candidate agent to bind to c-Kit or flt-3 and to bind to c-Kit or flt-3 and to potently modulate c-Kit or flt-3 activity. It is an indicator. In this embodiment, one component can be labeled. Thus, for example, when the competitor is labeled, the presence of the label in the wash solution indicates displacement by the factor. Alternatively, when the candidate agent is labeled, the presence of the label on the support indicates substitution.

  In an alternative embodiment, the candidate agent is added first, with incubation and washing, followed by the competitor. The absence of binding by this competitor may indicate that the candidate agent binds with high affinity to c-Kit or flt-3. Thus, when the candidate agent is labeled, the presence of this label on the support is linked to the lack of binding of the competitor, indicating that the candidate agent is capable of binding to c-Kit or flt-3. Can show.

  Identifying the binding site of c-Kit or flt-3 can be valuable. This can be done in various ways. In one embodiment, once c-Kit or flt-3 is identified to bind to a candidate agent, the c-Kit or flt-3 is fragmented or modified. This assay is then repeated until the components necessary for binding are identified.

  Modulation is tested by screening for candidate factors that allow modulation of the activity of c-Kit or flt-3, which comprises combining the candidate factors with c-Kit or flt-3 as described above, And measuring a change in the biological activity of the c-Kit or flt-3. Thus, in this embodiment, the candidate agent, as defined herein, binds (although this may not be necessary) and changes in biological or biochemical activity. Both should be done. This method includes both in vitro screening methods and in vivo screening of cells for changes in cell viability, morphology, etc.

  Alternatively, differential screening can be used to identify drug candidates that bind to native c-Kit or flt-3 but cannot bind to modified c-Kit or flt-3.

  Positive and negative controls can be used in the assay. For example, all controls and all test samples are performed at least three times to obtain statistically significant results. Sample incubation is sufficient time for binding of the agent to the protein. Following incubation, the sample is washed free of non-specific binding material and the amount of binding (usually labeled agent) is measured. For example, if a radiolabel is used, the sample can be counted in a scintillation counter to determine the amount of bound compound.

  A variety of other reagents can be included in the screening assay. These included reagents (such as salts, neutral proteins (eg, albumin), surfactants, etc.) may facilitate optimal protein-protein binding and / or non-specific or background interactions. Can be used to reduce. Reagents that improve the efficiency of the assay in other ways (eg, protease inhibitors, nuclease inhibitors, antimicrobial agents, etc.) can also be used. The mixture of components can be added in any order so as to provide the requisite binding.

(Abbreviations and their definitions)
The following abbreviations and terms have the meanings specified below throughout this specification:

.

(Synthesis of compounds)
Schemes 1-2 depict general synthetic routes for the compounds of the present invention, but are not to be construed as limited thereto. Specific examples are described following this general synthetic route. With reference to these general routes and the description of specific examples below, one skilled in the art can prepare the compounds of the invention as described.

Scheme 1 generally shows that compounds of formula I can be prepared, for example, via a convergent route. For example, ring A and ring B can be linked via functionalities a ′ and b ′, respectively. Functionalities a ′ and b ′ are used to build a linking group between ring A and ring B. Typically, although not necessarily, such linking groups include functionality according to Formula I (eg, L ¹ , L ² and R ⁴ ) along with a 1,3-diketo moiety. Such 1,3-diketones are converted to the corresponding pyrazines, typically using hydrazine, according to Formula I. While Scheme 1 depicts the functionality according to Formula I introduced at a particular stage of the synthesis (eg, L ¹ , L ² , R ¹ , R ² and R ⁴ ), those skilled in the art Such functionality depends on the nature of the functionality and the chemical reactions necessary to introduce or protect the functionality, and any of the various stages of the synthetic procedure used to produce a particular compound. Understand that it can be introduced or operated.

.

Scheme 2 shows another example using terminology consistent with Scheme 1. In this case, a linear approach is used, where the pyrazole ring and linker L ² are added onto ring B via functionality b ′. In general, but not necessarily, radicals containing 1,3-diketo moieties are added to ring B using b ′. This pyrazole ring is then introduced as depicted in connection with Scheme 1. Once this pyrazole is prepared, functionality c ′ is used to couple ring A, thereby forming linking group L ¹ and producing a compound according to Formula I. The order of the above steps can be varied, i.e., ring A and pyrazole can first be linked, and then ring B can be added to pyrazole to produce compounds of formula I. Again, while Scheme 2 depicts the functionality according to Formula I introduced at a particular stage of the synthesis (eg, L ¹ , L ² , R ¹ , R ² and R ⁴ ), One skilled in the art will appreciate that such functionality can be introduced or manipulated at any of the various stages of the synthetic procedure.

.

  Those skilled in the art will be familiar with the statements relating to Schemes 1-2; in the following, typical chemical reactions used to produce compounds according to Schemes 1-2 and Formula I are provided. To understand the. Those skilled in the art will also understand that there are other combinations of processes and chemical reactions that can be used to produce the compounds of the present invention.

  The following examples not only describe in more detail the manner of using the present invention described above, but serve to illustrate the best mode contemplated for carrying out various aspects of the present invention. It will be understood that these examples are not intended to limit the true scope of the invention in any way, but rather are provided for illustrative purposes. The contents of all references cited herein are hereby incorporated by reference.

Example 1
(4-{(E) -2- [3- (3-chlorophenyl) -1H-pyrazol-5-yl] ethenyl} phenol)

(2Z, 4E) -1- (3-Chlorophenyl) -3-hydroxy-5- (4-hydroxyphenyl) penta-2,4-dien-1-one: methyl 3-chlorobenzoate (0.677 g, 3 .97 mmol) and 4-hydroxybenzylideneacetone (0.644 g, 3.97 mmol) in anhydrous DMF (20 ml) at 0 ° C. was added NaH (60% dispersion, 0.477 g, 11.9 mmol). The reaction was warmed to room temperature overnight, quenched with saturated aqueous NH ₄ Cl, and neutralized with 1M HCl. The reaction was diluted with ethyl acetate (80 ml) and the organic layer was washed successively with saturated aqueous NaHCO ₃ and brine. The organic phase was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the condensation product as a yellow oil (0.717 g, 60% yield).

(2Z, 4E) -1- (3-Chlorophenyl) -3-hydroxy-5- (4-hydroxyphenyl) penta-2,4-dien-1-one (0.717 g, 2 in 2 ml of absolute ethanol) .39 mmol) and a catalytic amount of acetic acid in a sealed tube, 4-{(E) -2- [3- (3-chlorophenyl) -1H-pyrazol-5-yl] ethenyl} phenol: hydrazine dihydro-chloride (0.263 g, 2.50 mmol) was added. The reaction tube was sealed and heated to 80 ° C. After 12 hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in a small amount of methanol, precipitated with water, and the solid was collected by vacuum filtration to give the title compound as a yellow solid (288 mg, 41% yield): ¹ H NMR (400 MHz , CD ₃ OD): δ 7.79 (bs, 1H), 7.68 (bd, J = 7.6 Hz, 1H), 7.37 (m, 3H), 7.29 (bd, J = 7. 6 Hz, 1H), 7.12 (d, J = 16.4 Hz, 1H), 6.86 (d, J = 16.4 Hz, 1H), 6.81 (bs, 1H), 6.77 (m, _{2H); C 17 H 13 ClN} 2 O for the ^{MS (EI): 297.1 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic techniques and / or replacing with alternative reagents:
4-[(E) -2- (3-Phenyl-1H-pyrazol-5-yl) ethenyl] phenol: ¹ H NMR (400 MHz, CD ₃ OD): δ 7.76 (bs, 2H), 7.37 (M, 4H), 7.31 (bs, 1H), 7.12 (d, J = 16.4 Hz, 1H), 6.87 (bs, J = 16.8 Hz, 1H), 6.77 (m _{, 3H); C 17 H 14} N 2 O MS for ^{(EI): 263.1 (MH +} ).

4-{(E) -2- [3- (4-Chlorophenyl) -1H-pyrazol-5-yl] ethenyl} phenol: ¹ H NMR (400 MHz, CD ₃ OD): δ 7.74 (bs, 2H) , 7.38 (m, 4H), 7.11 (d, J = 16.8 Hz, 1H), 6.87 (bd, J = 16.4 Hz, 1H), 6.76 (m, 3H); C ₁₇ H ₁₃ ClN ₂ O for the ^{MS (EI): 297.1 (MH} +).

4-{(E) -2- [3- (2-Chlorophenyl) -1H-pyrazol-5-yl] ethenyl} phenol: ¹ H NMR (400 MHz, CD ₃ OD): δ 7.68 (bs, 1H) 7.49 (bs, 1H), 7.39 (m, 2H), 7.35 (m, 2H), 7.12 (d, J = 16.4 Hz, 1H), 6.90 (bd, J = 16.4Hz, 1H), 6.82 ( bs, 1H), 6.78 (m, 2H); C 17 H 13 ClN 2 O for the ^{MS (EI): 297.1 (MH} +).

4-{(E) -2- [3- (1-benzothien-2-yl) -1H-pyrazol-5-yl] ethenyl} phenol: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.62 (Bs, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.39-7 .30 (m, 4H), 7.13 (d, J = 16.4 Hz, 1H), 6.89 (s, 1H), 6.88 (d, J = 16.4 Hz, 1H), 6.78 _{(m, 2H); C 19} H 14 N 2 OS MS for ^{(EI): 319.1 (MH +} ).

4-{(E) -2- [3- (3,4-dichlorophenyl) -1H-pyrazol-5-yl] ethenyl} phenol: ¹ H NMR (400 MHz, CD ₃ OD): δ 7.95 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.0, 2.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.37 (m, 2H) ), 7.12 (d, J = 16.4 Hz, 1H), 6.87 (d, J = 16.4 Hz, 1H), 6.84 (s, 1H), 6.76 (m, 2H); _{C 17 H 12 Cl 2 N 2} O for the MS (EI): 331.01 (M +).

4-{(E) -2- [3- (5-Chloro-1-benzofuran-2-yl) -1H-pyrazol-5-yl] ethenyl} phenol: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.63 (bs, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.37 (m, 2H), 7 .31 (dd, J = 8.4, 2.4 Hz, 1H), 7.17 (d, J = 16.4 Hz, 1H), 7.16 (s, 1H), 6.91 (s, 1H) , 6.89 (d, J = 16.4 Hz, 1H), 6.77 (m, 2H); MS (EI) for C ₁₉ H ₁₃ ClN ₂ O ₂ : 337.1 (MH ⁺ ).

4-{(E) -2- [3- (1-benzofuran-2-yl) -1H-pyrazol-5-yl] ethenyl} phenol: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.63 (Bs, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.37 (m, 2H), 7.27 (m , 2H), 7.17 (s, 1H), 7.16 (d, J = 16.4 Hz, 1H), 6.89 (s, 1H), 6.89 (d, J = 16.4 Hz, 1H). _{), 6.77 (m, 2H)} ; C 19 H 14 N 2 for _{O 2} in ^{MS (EI): 303.1 (MH} +).

4-{(E) -2- [5- (2-fluorophenyl) -1H-pyrazol-3-yl] ethenyl} phenol: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.81 (m, 2H), 7.36 (d, 2H), 7.24 (m, 2H), 7.08 (d, 1H), 6.88 (d, 1H), 6.86 (s, 1H), 6. _{75 (d, 2H); C} 17 H 13 N 2 oF MS for ^{(EI): 281.1 (MH +} ).

4-{(E) -2- [5- (3-Fluorophenyl) -1H-pyrazol-3-yl] ethenyl} phenol: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.63 (d, 1H), 7.58 (d, 1H), 7.44 (m, 1H), 7.36 (d, 2H), 7.13 (m, 1H), 7.09 (d, 1H), 6. 94 (s, 1H), 6.85 (d, 1H), 6.78 (d, 2H): C 17 H 13 N 2 oF MS for ^{(EI): 281.1 (MH +} ).

4-{(E) -2- [5- (4-Fluorophenyl) -1H-pyrazol-3-yl] ethenyl} phenol: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.80 (t, 2H), 7.36 (d, 2H), 7.23 (t, 2H), 7.07 (d, 1H), 6.88 (d, 1H), 6.85 (s, 1H), 6. _{74 (d, 2H); C} 17 H 13 N 2 oF MS for ^{(EI): 281.1 (MH +} ).

4-((E) -2- {5- [2- (methyloxy) phenyl] -1H-pyrazol-3-yl} ethenyl) phenol: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.77 (Dd, 1H), 7.38 (d, 2H), 7.31 (dt, 1H), 7.11 (d, 1H), 7.00 (dt, 1H), 6.91 (d, 1H) , 6.90 (s, 1H), 3.90 (s, 3H); C 18 H 16 N 2 for _{O 2} in ^{MS (EI): 293.1 (MH} +).

4-((E) -2- {5- [3- (methyloxy) phenyl] -1H-pyrazol-3-yl} ethenyl) phenol: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.35 (m, 5H), 7.08 ( d, 1H), 6.88 (m, 3H), 6.76 (d, 2H), 3.80 (s, 3H); C 18 H 16 N 2 O 2 MS (EI) for: 293.1 (MH ^<+> ).

(Example 2)
(4-{(E) -2- [3- (1H-Benzimidazol-2-yl) -1H-pyrazol-5-yl] ethenyl} phenol)

To a solution of dimethyl oxalate (0.375 g, 3.2 mmol) and 4-hydroxybenzylideneacetone (0.515 g, 3.2 mmol) in anhydrous DMF (10 ml) at 0 ° C., (2Z, 4E) -3-hydroxy- Methyl 5- (4-hydroxyphenyl) penta-2,4-dienoate: NaH (60% dispersion, 0.183 g, 7.6 mmol) was added. The reaction was warmed to room temperature overnight, quenched with saturated aqueous NH ₄ Cl, and neutralized with 1M HCl. The reaction was diluted with ethyl acetate (80 ml) and the organic layer was washed successively with saturated aqueous NaHCO ₃ and brine. The organic phase was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the condensation product as a yellow oil (0.391 g, 50% yield).

1H-pyrazole-3-carboxylic acid, 5-[(E) -2- (4-hydroxyphenyl) ethenyl] -methyl ester: (2Z, 4E) -3-hydroxy-5- (in anhydrous ethanol (8 ml) Hydrazine (0.079 g, 1.6 mmol) was added to a sealed tube filled with methyl 4-hydroxyphenyl) penta-2,4-dienoate (0.391 g, 1.6 mmol) and a catalytic amount of acetic acid. The reaction tube was sealed and heated to 80 ° C. After 12 hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in a small amount of methanol, precipitated with water, and the solid was collected by vacuum filtration to give the title compound (240 mg, 41% yield): ¹ H NMR (400 MHz, CD ₃ OD): δ 13.15 (bs, 1H), 7.37 (d, J = 8.59 Hz, 1H), 7.18 (d, J = 16.6 Hz, 1H), 6.87 (s, 1H), 6. 85 (d, J = 16.6 Hz, 1H), 6.78 (d, J = 8.59 Hz, 1H), 3.80 (s, 3H).

1H-pyrazole-3-carboxylic acid, 5-[(E) -2- (4-hydroxyphenyl) ethenyl] -methyl ester (1.52 g, 6.22 mmol) in THF (50 ml) and H ₂ O (12. To the solution was added 5-[(E) -2- (4-hydroxyphenyl) ethenyl] -1H-pyrazole-3-carboxylic acid: lithium hydroxide hydrate (0.522 g, 12.44 mmol). . The reaction mixture was stirred at room temperature overnight. THF was removed with a rotary evaporator. The residue was neutralized with 3N HCl and the solid was collected by vacuum filtration to give the title compound (1.2 g, 84% yield).

  N- (2-aminophenyl) -3-[(E) -2- (4-hydroxyphenyl) ethenyl] -1H-pyrazole-5-carboxamide: 1,2-diaminobenzene (0.141 g, 1.31 mmol) , 5- [2 [(4-hydroxyphenyl) -vinyl] -2H-pyrazole-3-carboxylic acid (0.301 g, 1.31 mmol) and HOBt (0.266 g, 1.97 mmol) in anhydrous DMF (7 ml) To the solution was added 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDCI, 0.377 g, 1.97 mmol). The reaction was stirred at room temperature under nitrogen. After 12 hours, the reaction was concentrated in vacuo and precipitated from methanol with a small amount of water. The solid was collected by vacuum filtration and further purified by reverse phase HPLC (which uses a water-acetonitrile gradient (0.1% TFA)) to give the corresponding amide (44 mg, 10% yield). It was.

4-{(E) -2- [3- (1H-Benzimidazol-2-yl) -1H-pyrazol-5-yl] ethenyl} phenol: N- (2-aminophenyl) -3-[(E) A sealed tube filled with a solution of -2- (4-hydroxyphenyl) ethenyl] -1H-pyrazole-5-carboxamide (0.044 g, 1.36 mmol) in xylene (1.0 ml) was charged with glacial acetic acid (1.0 ml). And heated to 100 ° C. After 12 hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase HPLC, which uses a water-acetonitrile gradient (0.1% TFA) to give the title benzimidazole (10 mg, 25% yield) as a white solid: ¹ 1 H NMR (400 MHz, CD ₃ OD): δ 7.59 (bs, 2H), 7.41 (m, 2H), 7.25 (m, 2H), 7.16 (d, J = 16.4 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J = 16.4 Hz, 1H), 6.79 (m, 2H); MS (EI) for C ₁₈ H ₁₄ N ₄ O: 303.1 (MH ^<+> ).

(Example 3)
(4-((E) -2- {3- [6- (4-Methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyrazol-5-yl} ethenyl) phenol)

N- [2-amino-5- (4-methylpiperazin-1-yl) phenyl] -3-[(E) -2- (4-hydroxyphenyl) ethenyl] -1H-pyrazole-5-carboxamide: 5- (4-Methyl-piperazin-1-yl) -1,2-aminobenzene (0.085 g, 0.41 mmol), 5- [2 [(4-hydroxyphenyl) -vinyl] -2H-pyrazole-3-carbon To a solution of acid (0.047 g, 0.21 mmol) and DMAP (0.050 g, 0.41 mmol) in anhydrous DMF (2 ml) was added EDCI (0.078 g, 0.41 mmol) at room temperature. After 12 hours, the reaction was concentrated in vacuo to give the crude product.

4-((E) -2- {5- [5- (4-Methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyrazol-3-yl} ethenyl) phenol: Crude N 0.22 mmol of [2-amino-5- (4-methylpiperazin-1-yl) phenyl] -3-[(E) -2- (4-hydroxyphenyl) ethenyl] -1H-pyrazole-5-carboxamide , In a solution of AcOH: xylene (1: 1, 2 ml), heated to 100 ° C. in a sealed tube. After 12 hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase HPLC, which uses a water-acetonitrile gradient (0.1% TFA) to give the title benzimidazole (12 mg, 14% yield) as a dark purple solid: ¹ 1 H NMR (400 MHz, CD ₃ OD): δ 7.89 (s, 1H), 7.65 (bs, 1H), 7.36 (m, 2H), 7.23 (bs, 1H), 7.14 (Bd, J = 16.4 Hz, 2H), 6.86 (bd, J = 15.2 Hz, 1H), 6.75 (m, 2H), 3.92 (bd, J = 11.6 Hz, 2H) 3.65 (bd, J = 11.2 Hz, 2H), 3.39-3.21 (m, 3H), 2.99 (s, 3H), 2.90 (bt, J = 12.4 Hz, _{1H); C 23 H 24 N} 6 O for the ^{MS (EI): 401.2 (MH} +).

Example 4
(4-((E) -2- {3- [4- (4-Methylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} ethenyl) phenol)

4-((E) -2- {3- [4- (4-Methylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} ethenyl) phenol: 4-{(E) -2- [ 3- (4-Chlorophenyl) -1H-pyrazol-5-yl] ethenyl} phenol (0.097 g, 0.33 mmol), NaOtBu (0.110 g, 1.14 mmol) and acetate (2′-di-tertiary) To a suspension of butylphosphino-1,1′-biphenyl-2-yl) palladium (0.015 g, 33 μmol, 10 mol%) in anhydrous toluene (1.5 ml), N-methylpiperazine (50 μL, 0.49 mmol) And heated to 80 ° C. After 24 hours, the reaction was cooled to room temperature, diluted with methanol, and filtered through a celite pad. The filtrate was concentrated in vacuo and the residue was purified by reverse phase HPLC (using a water-acetonitrile gradient (0.1% TFA)) to give the title compound (10 mg, yield) as an off-white solid. 9%): ¹ H NMR (400 MHz, CD ₃ OD): δ 7.71 (m, 2H), 7.40 (m, 2H), 7.20 (d, J = 16.4 Hz, 1H) ), 7.10 (m, 2H), 6.87 (d, J = 16.4 Hz, 1H), 6.84 (s, 1H), 6.79 (m, 2H), 3.95 (bd, J = 14.4 Hz, 2H), 3.63 (bd, J = 11.2 Hz, 2H), 2.28 (m, 2H), 3.10 (bt, J = 13.2 Hz, 2H), 2. _{99 (s, 3H); C} 22 H 24 N 4 O for the ^{MS (EI): 361.2 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic techniques and / or replacing with alternative reagents:
4-((E) -2- {3- [3- (4-Methylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} ethenyl) phenol: ¹ H NMR (400 MHz, CD ₃ OD) : Δ 7.50-7.45 (m, 4H), 7.36 (bd, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.21 (dd, J = 8.0) , 2.4 Hz, 1H), 6.89 (d, J = 16.4 Hz, 1H), 6.82 (m, 2H), 3.99 (bd, J = 14.0 Hz, 2H), 3.65 (Bd, J = 12.0 Hz, 2H), 3.31 (m, 2H), 3.20 (dt, J = 13.6, 1.6 Hz, 2H), 2.99 (s, 3H); C ₂₂ H ₂₄ N ₄ O MS for ^{(EI): 361.2 (MH +} ).

(Example 5)
(2- (Methyloxy) -4-[(E) -2- (5-phenyl-1H-pyrazol-3-yl) ethenyl] phenol)

4- (4-Hydroxy-3-methoxy-phenyl) but-3-en-2-one: To a solution of acetone (15.30 g, 263.76 mmol) in a mixture of ethanol (35 ml) and water (15 ml), Sodium hydroxide (2.90 g, 72.54 mmol) and 4-hydroxy-3-methoxybenzaldehyde (5.01 g, 32.97 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours. The reaction was cooled to 0 ° C. and quenched with 2.0 N hydrochloric acid until the solution was slightly acidic. This solution was extracted with ethyl acetate (4 × 100 ml). The combined organic layers were washed with water (50 ml) and saturated aqueous sodium chloride solution (50 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4- (4-hydroxy-3-methoxy-phenyl) but-3-en-2-one (5. 52 g, was obtained 87% _{yield): C 11 H 12 O 3} MS for ^{(EI): 193 (MH +} ).

4- {4-[(tertiary butyl-dimethyl-silanyloxy) -methyl} -3-methoxy-phenyl} -but-3-en-2-one: 4- (4-hydroxy-3-methoxy-phenyl) To a solution of but-3-en-2-one (4.402 g, 22.93 mmol) in N, N-dimethylformamide (28.5 ml) was added imidazole (1.71 g, 25.22 mmol) and tert-butyldimethylchloride. Silyl (3.8 g, 25.22 mmol) was added. The reaction was stirred for 4 hours, then diluted with ethyl acetate (300 ml) and washed with water (50 ml), saturated aqueous sodium bicarbonate (40 ml) and saturated aqueous sodium chloride (50 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product. Column purification on silica (8: 2 hexane / ethyl acetate) gave 4- {4-[(tertiary butyl-dimethyl-silanyloxy) -methyl} -3-methoxy-phenyl} -buta-3 as a solid. -En-2-one (5.24 g, 73% yield) was obtained: ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.32 (d, 2H), 6.92 (m, 2H), 6.78 (d, 1H), 6.53 (d, 2H), 3.78 (s, 3H), 2.28 (s, 3H), 0.92 (s, 9H), 0.16 (s , 6H).

5- (Hydroxy-3-methoxy-phenyl) -1-phenyl-pent-4-ene-1,3-dione: N, N-dimethylformamide of sodium hydride (60%, 0.13 g, 3.28 mmol) To a slurry solution of 4- {4-[(tertiary butyl-dimethyl-silanyloxy) -methyl} -3-methoxy-phenyl} -but-3-en-2-one (0.50 g, 1.54 mmol) and methyl benzoate (0.26 g, 1.97 mmol) were added. The reaction was stirred at 0 ° C. for 1 hour. The reaction mixture was removed from the ice bath and heated at 60 ° C. for 1 hour. The reaction was cooled to room temperature and slowly quenched with 1.0 N aqueous hydrochloric acid (2.0 ml). Excess tetrabutylammonium fluoride was added to the above solution to deprotect the silyl group. The reaction was diluted with ethyl acetate (200 ml) and washed with water (3 × 60 ml) and saturated aqueous sodium chloride solution (50 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to give an impure crude product. Purification on silica (9: 1-7: 3 hexane / ethyl acetate) gave 5- (hydroxy-3-methoxy-phenyl) -1-phenyl-pent-4-ene-1,3-dione as a solid. (0.14 g, 30% yield) was obtained: MS (EI) for C ₁₈ H ₁₆ O ₄ : 297 (MH ⁺ ).

2- (Methyloxy) -4-[(E) -2- (5-phenyl-1H-pyrazol-3-yl) ethenyl] phenol: 5- (hydroxy-3-methoxy-phenyl) in a sealed tube A mixture of -1-phenyl-pent-4-ene-1,3-dione (0.14 g, 0.48 mmol) and hydrazine monohydrate (0.02 g, 0.48 mmol) was added to ethanol (24 ml) and acetic acid. (1 drop) was added. The reaction was heated at 65-70 ° C. overnight. The solvent was removed under reduced pressure to obtain a crude product. Purification on triethylamine treated silica (1: 1 hexane / ethyl acetate) gave a mixture of two products. Purification by reverse phase HPLC gave 2- (methyloxy) -4-[(E) -2- (5-phenyl-1H-pyrazol-3-yl) ethenyl] phenol (0.015 g) as the trifluoroacetate salt. , Yield 10%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.21 (br s, 2H), 7.78 (br s, 2H), 7.42 (m, 3H) , 7.20 (br d, 1H) , 6.94 (m, 6H), 3.92 (s, 3H); C 18 H 16 N 2 for _{O 2} in ^{MS (EI): 293 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic techniques and / or replacing with alternative reagents:
2- (Methyloxy) -4-((E) -2- {5-[(E) -2-phenylethenyl] -1H-pyrazol-3-yl} ethenyl) phenol: ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.42 (br d, 2H), 7.30 (m, 3H), 7.15 (m, 2H), 7.02 (m, 3H), 6.85 (m, 3H), 6.68 (br s, 1H), 3.85 (s, 3H); C 20 H 18 N 2 for _{O 2} in ^{MS (EI): 319 (MH} +).

4-((E) -2- {3-[(E) -2- (4-chlorophenyl) ethenyl] -1H-pyrazol-5-yl} ethenyl) -2- (methyloxy) phenol: ¹ H NMR ( 400 MHz, CDCl ₃ ): δ 7.38 (br d, 2H), 7.32 (br d, 2H), 7.20 (m, 3H), 6.90 (m, 6H), 6.62 (br _{s, 1H), 3.95 (s} , 3H); C 20 H 17 N 2 O 2 for Cl of ^{MS (EI): 353,355 (MH} +).

4-((E) -2- {3-[(E) -2- (4-fluorophenyl) ethenyl] -1H-pyrazol-5-yl} ethenyl) -2- (methyloxy) phenol: ¹ H NMR (400 MHz, d-MeOH): δ 7.46 (m, 2H), 7.08 (m, 5H), 6.90 (m, 2H), 6.75 (d, 1H), 6.68 (br d, 2H), 3.82 (s , 3H); MS (EI) forC 20 H 17 N 2 O 2 F: 337 (MH +).

4-((E) -2- {3-[(E) -2- (2,4-difluorophenyl) ethenyl] -1H-pyrazol-5-yl} ethenyl) -2- (methyloxy) phenol: ¹ 1 H NMR (400 MHz, d-MeOH): δ 7.42 (m, 1H), 7.25 (d, 1H), 7.15 (m, 3H), 7.02 (m, 3H), 6.90 (d, 1H), 6.78 ( br t, 2H), 3.92 (s, 3H); C 20 H 16 N 2 O 2 MS for _{F 2 (EI): 355 (} MH +).

4-((E) -2- {5-[(E) -2-phenylethenyl] -1H-pyrazol-3-yl} ethenyl) phenol: ¹ H NMR (400 MHz, d-MeOH): δ 7. 64 (br d, 2H), 7.44 (m, 7H), 7.12 (br t, 2H), 6.87 (m, 3H); C 19 H 16 N 2 O MS for (EI): 289 (MH ^<+> ).

4-[(E) -2- (3-Pyridin-3-yl-1H-pyrazol-5-yl) ethenyl] phenol: ¹ H NMR (400 MHz, d-MeOH): δ 9.20 (br s, 1H ), 8.85 (d, 1 H), 8.65 (br s, 1 H), 8.20 (br s, 1 H), 7.42 (d, 2 H), 7.20 (d, 1 H), 7 .04 (s, 1H), 6.85 (d, 1H), 6.80 (d, 2H); C 16 H 13 N 3 O MS for ^{(EI): 264 (MH +} ).

4-[(E) -2- (3-Pyridin-4-yl-1H-pyrazol-5-yl) ethenyl] phenol: ¹ H NMR (400 MHz, d-MeOH): δ 8.64 (br d, 1H ), 8.50 (br t, 1H), 8.34 (br d, 1H), 7.82 (br t, 1H), 7.40 (d, 2H), 7.18 (m, 2H), 6.90 (d, 1H), 6.80 (d, 2H); C 16 H 13 N 3 O MS for ^{(EI): 264 (MH +} ).

4-[(E) -2- (5-Naphthalen-2-yl-1H-pyrazol-3-yl) ethenyl] phenol: ¹ H NMR (400 MHz, d-MeOH): δ 8.38 (br s, 1H ), 7.94 (m, 5H), 7.60 (m, 2H), 7.52 (m, 3H), 7.38 (s, 1H), 6.92 (d, 1H), 6.84 _{(d, 2H); C 21} H 16 N 2 O for ^{MS (EI): 313 (MH} +).

4-[(E) -2- (5-pyridin-2-yl-1H-pyrazol-3-yl) ethenyl] phenol: ¹ H NMR (400 MHz, d-MeOH): δ 8.70 (d, 1H) , 8.62 (t, 1H), 8.44 (d, 1H), 7.92 (t, 1H), 7.40 (d, 2H), 7.20 (d, 2H), 6.90 ( _{d, 1H), 6.80 (d} , 2H); C 16 H 13 N 3 O MS for ^{(EI): 264 (MH +} ).

4-[(E) -2- (5-biphenyl-3-yl-1H-pyrazol-3-yl) ethenyl] phenol: ¹ H NMR (400 MHz, d-MeOH): δ 7.42 (m, 1H) 7.25 (d, 1H), 7.15 (m, 3H), 7.02 (m, 3H), 6.90 (d, 1H), 6.78 (brt, 2H), 3.92 _{(s, 3H); C 20} H 16 N 2 O 2 F 2
MS (EI) for: 355 (MH ^<+> ).

1,4-Dimethylethyl (4- {3-[(E) -2-phenylethenyl] -1H-pyrazol-5-yl} phenyl) carbamate: ¹ H NMR (400 MHz, d-MeOH): δ 7 .66 (br d, 2H), 7.50 (m, 5H), 7.35 (br t, 3H), 7.28 (br d, 1H), 7.20 (d, 1H), 7.08 (d, 1H), 6.82 ( s, 1H), 1.50 (s, 9H); C 22 H 23 N 3 for _{O 2} in ^{MS (EI): 362 (MH} +).

(Example 6)
(2- {5-[(E) -2-phenylethenyl] -1H-pyrazol-3-yl} -1-benzofuran-6-ol)

4-formyl-3-hydroxyphenyl acetate: sodium hydroxide (1.00 g, 25.08 mmol) in ethanol (20 ml) solution of 4-formylbenzene-1,3-diyl diacetate (5.56 g, 25.08 mmol) ) In water (12 ml) was added. The reaction was stirred overnight at room temperature. The reaction was carefully neutralized with a 2.0N aqueous solution of hydrochloric acid (12.8 ml) at 0 ° C. and diluted with ethyl acetate (400 ml). The organic layer was washed with water (60 ml) and saturated aqueous sodium chloride solution (50 ml), dried over magnesium sulfate, filtered and concentrated to give the product (2.01 g, 44% yield) as a gray solid. ¹ H NMR (400 MHz, d-MeOH): δ 9.90 (s, 1H), 7.68 (d, 1H), 6.80 (d, 1H), 6.75 (s, 1H) ), 4.82 (br s, 1H), 2.20 (s, 3H).

  2-acetyl-1-benzofuran-6-yl acetate: A solution of 4-formyl-3-hydroxyphenyl acetate (1.74 g, 9.67 mmol) in acetonitrile (10 ml) and solid anhydrous potassium carbonate (1.33 g, 9. 67 mmol) was added and stirred at room temperature for 30 minutes before chloroacetone (0.98 g, 9.67 mmol) was added slowly via syringe. A reflux condenser was attached and the reaction was heated to reflux overnight, then cooled to room temperature and diluted with ethyl acetate (350 ml). The organic layer was washed with 2.0 N aqueous HCl (100 ml), dried with saturated aqueous sodium chloride (60 ml), magnesium sulfate, filtered and concentrated to give the crude product. Purification on silica (9: 1-7: 3, hexane / ethyl acetate) gave the desired product with the product without acetate groups. The total weight of the resulting mixture was 0.4421 g. This mixture was taken to the next step without further purification.

(4E) -1- (6-Hydroxy-1-benzofuran-2-yl) -5-phenylpent-4-ene-1,3-dione: crude 2-acetyl-1-benzofuran-6-yl acetate (0 Lithium diisopropylamine (2.0 N THF solution, 1.63 ml, 3.25 mmol) was added to a solution of .23 g) in tetrahydrofuran (5 ml) at -78 ° C. The mixture was stirred at the same temperature for 20 minutes before cinnamoyl chloride (0.22 g, 1.3 mmol) was added. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was treated with 1.0 N aqueous hydrochloric acid (10 ml) at 0 ° C. and diluted with ethyl acetate (250 ml). The organic layer was washed with 2N aqueous hydrochloric acid (100 ml), saturated aqueous sodium chloride (60 ml), dried over magnesium sulfate, filtered and concentrated to give the crude product. Purification on silica (gradient 8: 2-6: 4, hexane / ethyl acetate) gave the product (0.12 g, 30% yield) as a yellow solid: for C ₁₉ H ₁₄ O ₄ MS (EI): 307 (MH ^<+> ).

2- {5-[(E) -2-phenylethenyl] -1H-pyrazol-3-yl} -1-benzofuran-6-ol: (4E) -1- (6-hydroxy) in a sealed tube -1-benzofuran-2-yl) -5-phenylpent-4-ene-1,3-dione (0.48 mmol) and hydrazine monohydrate (0.02 g, 0.48 mmol) were added to ethanol ( 24 ml) and acetic acid (1 drop) were added. The reaction was stirred at 65-70 ° C. overnight. The solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by reverse phase HPLC. Fractions from the HPLC were combined, neutralized with 1.0 N aqueous sodium hydroxide and diluted with ethyl acetate (200 ml). The organic layer was washed with saturated aqueous sodium chloride solution (50 ml), dried over magnesium sulfate, filtered and concentrated to give the product (yield 11%): ¹ H NMR (400 MHz, CD ₃ Cl) : Δ 7.58 (brd, 2H), 7.35 (m, 4H), 7.25 (t, 2H), 7.10 (brd, 1H), 7.05 (brs, 1H), 6.94 (br d, 1H), 6.88 (br s, 1H), 6.75 (dd, 1H); C 19 H 14 N 2 for _{O 2} in ^{MS (EI): 303 (MH} +).

(Example 7)
(N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-[4- (3-phenyl-1H-pyrazol-5-yl) phenyl] urea)

{4-[(1Z) -1-hydroxy-3-oxo-3-phenylprop-1-en-1-yl] phenyl} 1,1-dimethylethyl carbamate: methyl benzoate (0.629 g, 4. 62 mmol) and 1,1-dimethylethyl (4-acetylphenyl) carbamate (N-BOC-4-aminoacetophenone 1.09 g, 4.62 mmol) in anhydrous DMF (20 ml) at 0 ° C. with NaH (60 % Dispersion, 0.388 g, 16.2 mmol) was added. The reaction was allowed to warm to room temperature overnight, then quenched with saturated aqueous NH ₄ Cl and neutralized with 1M HCl. The reaction was diluted with ethyl acetate (80 ml) and the organic layer was washed successively with saturated aqueous NaHCO ₃ and brine. The organic phase was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the condensation product as a yellow oil (1.31 g, 83% yield). This product was used in the next step without further purification.

4- (5-Phenyl-1H-pyrazol-3-yl) aniline: In a sealed tube filled with the above product (1.31 g, 3.87 mmol) in anhydrous ethanol (17 ml) and a catalytic amount of acetic acid, hydrazine Dihydrochloride (0.427 g, 4.00 mmol) was added. The reaction tube was sealed and heated to 85 ° C. After 12 hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in a small amount of methanol, precipitated with water, and the solid was collected by vacuum filtration to give the desired compound as a white solid (974 mg, 75% yield). Under the reaction conditions, the BOC group was removed: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.95 (m, 3H), 7.82 (m, 2H), 7.45 (m, 3H) ), 7.34 (m, 2H) , 7.23 (s, 1H), 2.30 (bs, 2H); C 15 MS for _{H 13 N 3 (EI):} 236.1 (MH +).

N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-[4- (5-phenyl-1H-pyrazol-3-yl) phenyl] urea: N- [4- (3-phenyl- 1H-pyrazol-5-yl) aminobenzene (0.102 g, 0.43 mmol) and 4-chloro-3-trifluoromethyl-phenyl isocyanate (0.096 g, 0.43 mmol) in anhydrous acetonitrile (2.0 ml) To the suspension was added triethylamine (64 ml, 0.45 mmol) at room temperature. After 12 hours, the reaction was concentrated in vacuo and purified by reverse phase HPLC (using a water-acetonitrile gradient (0.1% TFA)) to give the title compound as a white solid ( 23 mg, yield 16%) were obtained: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.24 (s, 1 H), 9.01 (s, 1 H), 8.11 (d, J = 2.0 Hz, 1H), 7.81 (m, 2H), 7.74 (m, 2H), 7.62 (m, 2H), 7.53 (m, 2H), 7.42 (t, J = 8.0Hz, 2H), 7.32 ( t, J = 7.6Hz, 1H), 7.10 (s, 1H); C 23 H 16 ClF 3 N 4 O MS for (EI): 457. 1 (MH ⁺ ).

The following compounds of the invention were prepared using the same or similar synthetic techniques and / or replacing with alternative reagents:
N-phenyl-N ′-[4- (3-phenyl-1H-pyrazol-5-yl) phenyl] urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.80 (bs, 1H), 8 .72 (bs, 1H), 7.81 (d, J = 7.2 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.44 (m, 3H), 7.29 (m, 3H), 7.08 (s, 1H), 6.96 (t, J = 7.2 Hz, 1H); C ₂₂ H ₁₈ N ₄ O for the ^{MS (EI): 355.1 (MH} +).

(Example 8)
(N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [4- (4-ethylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl } Phenyl) urea)

(2Z) -3- (4-Aminophenyl) -1- [4- (4-ethylpiperazin-1-yl) phenyl] -3-hydroxyprop-2-en-1-one: in anhydrous toluene (10 ml) Of {4- [3- (4-bromophenyl) -1-hydroxy-3-oxo-propenyl] -phenyl} -carbamic acid tert-butyl ester (0.842 g, 2.01 mmol), NaOtBu (0.483 g) , 5.03 mmol) and acetate (2′-di-t-butylphosphino-1,1′-biphenyl-2-yl) palladium (0.140 g, 0.30 mmol, 15 mol%) N-ethylpiperazine (334 μL, 2.62 mmol) was added. The reaction tube was sealed and heated to 110 ° C. After 24 hours, the reaction was cooled to room temperature, diluted with methanol, and filtered through a celite pad. The filtrate is concentrated in vacuo and the residue is purified by reverse phase HPLC, which uses a water-acetonitrile gradient (0.1% TFA) to give 3- (4-aminophenyl) as an off-white solid. ) -3-Hydroxy-1- [4- (4-ethylpiperazin-1-yl) -phenyl] -propenone (208 mg, 32% yield) was obtained. Note that the BOC group was removed during this purification: ¹ H NMR (400 MHz, CD ₃ OD): δ 7.97 (m, 2H), 7.85 (m, 2H), 7.10 ( m, 2H), 6.84 (s, 1H), 6.78 (m, 2H), 4.11 (bd, J = 12.0 Hz, 2H), 3.69 (bd, J = 10.4 Hz, 2H), 3.32-3.22 (m, 6H ), 1.41 (t, J = 5.4Hz, 3H); C 21 H 25 N 3 for _{O 2} in MS (EI): 352.1 ( MH ^<+> ).

4- {3- [4- (4-Ethylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} aniline: the above product (0.208 g, 0.59 mmol) in absolute ethanol (5 ml) And hydrazine dihydrochloride (0.093 g, 0.89 mmol) were added to a sealed tube filled with a catalytic amount of acetic acid. The reaction tube was sealed and heated to 85 ° C. After 12 hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in a small amount of methanol and precipitated with a solution of methylene chloride: hexane (1: 1). The solid was collected by vacuum filtration to give the corresponding pyrazole product (174 mg, 85% yield) as a yellow solid: ¹ H NMR (400 MHz, CD ₃ OD): δ 8.01 (m, 2H) ), 7.77 (m, 2H), 7.51 (m, 2H), 7.24 (s, 1H), 7.16 (m, 2H), 4.03 (bd, J = 12.0 Hz, 2H), 3.70 (bd, J = 10.4 Hz, 2H), 3.32-3.22 (m, 6H), 1.42 (t, J = 5.4 Hz, 3H); C ₂₁ H ₂₅ MS of the _{N 5 (EI): 348.1 (} MH +).

N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [4- (4-ethylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} Phenyl) urea: To a suspension of the above pyrazole (0.067 g, 0.19 mmol) and 4-chloro-3-trifluoromethyl-phenyl isocyanate (0.055 g, 0.25 mmol) in anhydrous acetonitrile (2.0 ml), At room temperature, triethylamine (35 μL, 0.25 mmol) was added. After 12 hours, the reaction was concentrated in vacuo and purified by reverse phase HPLC (using a water-acetonitrile gradient (0.1% TFA)) to give the title compound as a white solid ( 8 mg, yield 8%): ¹ H NMR (400 MHz, CD ₃ OD): δ 8.02 (bd, J = 2.8 Hz, 1H), 7.78 (m, 4H), 7.64 (Bd, J = 2.8 Hz, 1H), 7.61 (m, 2H), 7.51 (d, J = 10.8 Hz, 1H), 7.15 (m, 2H), 7.11 (bs) , 1H), 4.03 (bd, J = 12.0 Hz, 2H), 3.71 (bd, J = 10.4 Hz, 2H), 3.31 (m, 4H), 3.13 (m, 2H) ), 1.42 (t, J = 5.4 Hz, 3H); MS (EI) for C ₂₉ H ₂₈ ClF ₃ N ₆ O: 5 69.2 (MH ⁺ ).

The following compounds of the invention were prepared using the same or similar synthetic techniques and / or replacing with alternative reagents:
N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} Phenyl) urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.07 (d, J = 5.6 Hz, 1H), 7.74 (m, 4H), 7.61 (dd, J = 8 .4, 2.4 Hz, 1H), 7.54 (m, 3H), 7.07 (m, 3H), 3.92 (bd, J = 13.2 Hz, 2H), 3.52 (bd, J = 12.0 Hz, 2H), 3.17 (dt, J = 11.2, 2.0 Hz, 2H), 3.07 (bt, J = 12.0 Hz, 2H), 2.86 (s, 3H) _{; C 28 H 26 ClF 3 N} 6 O MS for ^{(EI): 556.2 (MH +} ).

N- (4- {3- [4- (4-Methylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} phenyl) -N ′-(2-phenylethyl) ethanediamide: ¹ H NMR ( 400 MHz, DMSO-d ₆ ): δ 7.85-7.58 (m, 7H), 7.26-7.13 (m, 6H), 6.92 (m, 4H), 3.81 (bs, 1H), 3.44 (bt, J = 6.8 Hz, 2H), 3.17 (m, 5H), 2.82 (t, J = 7.6 Hz, 2H), 2.48 (m, 2H) _{, 2.23 (s, 3H);} C 30 H 32 N 6 MS for _{O 2 (EI): 509.3 (} MH +).

N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [3- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} Phenyl) urea: ¹ H NMR (400 MHz, CD ₃ OD): δ 8.10 (d, J = 2.4 Hz, 1H), 7.81 (m, 2H), 7.67 (dd, J = 8. 8, 2.4 Hz, 1 H), 7.62 (m, 2 H), 7.57 (d, J = 8.8 Hz, 1 H), 7.53 (bs, 1 H), 7.42 (m, 2 H) 7.15 (s, 1H), 7.09 (m, 1H), 4.01 (bd, J = 13.2 Hz, 2H), 3.65 (bd, J = 12.0 Hz, 2H), 3 .32 (m, 2H), 3.17 (dt, J = 13.2, 1.6 Hz, 2H), 2.99 (s, 3H); C ₂₈ H ₂₆ C lF ₃ N ₆ O for the ^{MS (EI): 555.2 (MH} +).

N- (2,4-difluorophenyl) -N ′-(4- {3- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} phenyl) urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.09 (m, 1H), 7.73 (m, 4H), 7.51 (m, 2H), 7.28 (m, 1H), 7.07 (M, 2H), 7.03 (m, 1H), 7.00 (s, 1H), 3.92 (bd, J = 12.8 Hz, 2H), 3.52 (bd, J = 12.8 Hz) , 2H), 3.17 (dt, J = 12.4, 2.4 Hz, 2H), 3.05 (dt, J = 12.4, 2.4 Hz, 2H), 2.86 (s, 3H) _{; C 27 H 26 F 2 N} 6 O for the ^{MS (EI): 489.2 (MH} +).

N- [2,4-bis (methyloxy) phenyl] -N ′-(4- {5- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-3-yl} phenyl) Urea: ¹ H NMR (400 MHz, CH ₃ OH-d4): δ 8.80 (m, 2H), 7.70 (m, 1H), 7.50 (m, 2H), 6.50 (m, 5H) ), 3.95 (s, 3H), 3.85 (s, 3H), 3.78 (m, 4H), 2.68 (m, 4H), 2.40 (s, 3H); C ₂₉ H ₃₂ N ₆ O ₃ MS for ^{(EI): 513.2 (MH +} ).

N- [5-chloro-2- (methyloxy) phenyl] -N ′-(4- {5- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-3-yl} phenyl ) Urea: ¹ H NMR (400 MHz, CH ₃ OH-d4): δ 8.25 (s, 1H), 7.70 (dd, 4H), 7.60 (d, 2H), 7.00 (d, 2H), 6.80 (s, 1H). 3.95 (s, 3H), 3.38 (m, 4H), 2.60 (m, 4H), 2.40 (s, 3H); C 28 H 29 ClN 6 MS for _{O 2} (EI) : 517.2 (M).

N- (3,4-dimethylphenyl) -N ′-(4- {5- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-3-yl} phenyl) urea: ¹ H NMR (400 MHz, DMSO-d6): δ 13.0 (s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 7.60 (m, 7H), 7.30 ( m, 5H), 3.20 (m , 4H), 2.50 (m, 4H), 2.10 (m, 9H); C 29 H 32 N 6 MS for _{O 2} (EI): 481.3 (MH ⁺ ).

N- (4- {5- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-3-yl} phenyl) -N ′-[4- (phenyloxy) phenylurea: ¹ H NMR (400 MHz, DMSO-d6): δ 8.78 (br, 2H), 7.70 (m, 3H), 7.50 (m, 3H), 7.40 (m, 3H), 7.00 ( m, 8H), 3.20 (m , 4H), 2.50 (m, 4H), 2.20 (s, 3H); C 33 H 32 N 6 MS for _{O 2} (EI): 545.3 (MH ⁺ ).

N- (2,3-dihydro-1,4-benzodioxin-6-yl) -N ′-(4- {5- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazole- 3-yl} phenyl) urea: ¹ H NMR (400 MHz, CH ₃ OH-d4): δ 7.70 (m, 4H), 7.50 (d, 2H), 7.10 (m, 3H), 6 .90 (s, 1H), 6.80 (m, 2H), 4.20 (m, 4H), 3.90 (m, 2H), 3.60 (m, 2H), 3.30 (m, 2H), 3.10 (m, 2H ), 2.90 (s, 3H); C 29 H 30 N 6 O 3 MS for ^{(EI): 511.3 (MH +} ).

N- (5-fluoro-2-methylphenyl) -N ′-(4- {5- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-3-yl} phenyl) urea: ¹ H NMR (400 MHz, CH ₃ OH-d4): δ 7.70 (m, 5H), 7.60 (d, 2H), 7.20 (m, 3H), 6.90 (s, 1H), 6.80 (m, 1H), 4.00 (m, 2H), 3.60 (m, 2H), 3.30 (m, 2H), 3.10 (m, 2H), 2.90 (s) _{, 3H), 2.25 (s,} 3H); C 28 H 29 FN 6 O MS for ^{(EI): 485.3 (MH +} ).

Example 9
(N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [5- (4-ethylpiperazin-yl) -1H-benzimidazol-2-yl] -1H -Pyrazol-3-yl} phenyl) urea)

4- {5- [5- (4-Ethylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-3-yl} aniline: 4- (4-ethylpiperazin-1-yl) To a solution of) -benzene-1,2-diamine (as tetrahydrochloride) in anhydrous DMF (4 ml) was added triethylamine (509 μL, 3.62 mmol). After 5 minutes, to this diamine was added a solution of [4- (5-formyl-1H-pyrazol-3-yl) phenyl] carbamic acid tertiary butyl ester in anhydrous DMF (2 ml). The reaction flask was left open to the atmosphere and heated to 65 ° C. After 12 hours, the reaction was concentrated in vacuo, and the residue was purified by reverse phase HPLC (using a water-acetonitrile gradient (0.1% TFA)) as a magenta solid. The product (87 mg, 99% yield) was obtained. Note that the BOC group was removed during this purification: ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.90 (m, 2H), 7.71 (d, J = 8.8 Hz, 1H) , 7.46 (m, 2H), 7.42 (dd, J = 9.2, 2.0 Hz, 1H), 7.41 (s, 1H), 7.30 (d, J = 2.4 Hz, 1H), 4.01 (bd, J = 12.0 Hz, 2H), 3.74 (bd, J = 10.4 Hz, 2H), 3.35-3.27 (m, 4H), 3.23 ( m, 2H), 1.44 (t , J = 7.2Hz, 3H); C 22 H 25 for _{N 7} of ^{MS (EI): 388.2 (MH} +).

N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [5- (4-ethylpiperazin-yl) -1H-benzimidazol-2-yl] -1H— Pyrazol-3-yl} phenyl) urea: anhydrous DMSO (2.0 ml) of the above pyrazole (0.087 g, 0.18 mmol) and 4-chloro-3-trifluoromethyl-phenyl isocyanate (0.039 g, 0.18 mmol). ) To the solution was added triethylamine (250 μL, 1.78 mmol) at room temperature. After 12 hours, the reaction was concentrated in vacuo and purified by reverse phase HPLC (using a water-acetonitrile gradient (0.1% TFA)) to give the title compound as an off-white solid ( 46 mg, 43% yield) was obtained: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.81 (bs, 1H), 9.95 (s, 1H), 9.69 (s, 1H) , 8.14 (s, 1H), 7.78 (m, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.66 (m, 5H), 7.54 (s, 1H) ), 7.36 (bd, J = 9.2 Hz, 1H), 7.16 (s, 1H), 3.91 (bd, J = 11.2 Hz, 2H), 3.60 (bd, J = 10) .8 Hz, 2H), 3.19 (m, 6H), 1.30 (t, J = 7.2 Hz, 3H); C ₃₀ H ₂₈ ClF ₃ N ₈ O MS for (EI): 609.3 (M + ).

The following compounds of the invention were prepared using the same or similar synthetic techniques and / or replacing with alternative reagents:
N- (2,4-difluorophenyl) -N ′-(4- {3- [6- (4-ethylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole-3- Yl} phenyl) urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.04 (m, 1H), 7.69 (m, 2H), 7.64 (d, J = 9.2 Hz, 1H) ), 7.54 (m, 2H), 7.34 (s, 1H), 7.31 (dd, J = 9.2, 2.0 Hz, 1H), 7.17 (d, J = 2.0 Hz) , 1H), 7.11 (m, 1H), 6.93 (m, 1H), 3.88 (bd, J = 10.8 Hz, 2H), 3.61 (bd, J = 12.4 Hz, 2H) ), 3.18 (m, 6H) , 1.30 (t, J = 7.2Hz, 3H); C 29 H 28 F 2 N 8 O M for ^{(EI): 543.3 (MH +} ).

N- (3-ethylphenyl) -N ′-(4- {3- [5- (4-ethylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-3-yl} Phenyl) urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.77 (m, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 (m, 2H), 7.51 (s, 1H), 7.39 (dd, J = 9.2, 1.6 Hz, 1H), 7.35 (bs, 1H), 7.31 (bd, J = 8.0 Hz, 1H) ), 7.22 (m, 2H), 6.85 (bd, J = 5.6 Hz, 1H), 3.94 (bd, J = 9.2 Hz, 2H), 3.65 (bd, J = 8) .4 Hz, 2H), 3.22 (m, 4H), 3.14 (m, 2H), 3.10 (q, J = 7.2 Hz, 2H), 1.21 t, J = 7.2Hz, 3H) , 1.20 (t, J = 7.6Hz, 3H); C 31 H 34 N 8 O for the ^{MS (EI): 535.3 (MH} +).

N- (4- {3- [5- (4-Ethylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-3-yl} phenyl) -N ′-[3- ( Trifluoromethyl) phenyl] urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.0 (bs, 1H), 9.91 (s, 1H), 9.77 (s, 1H), 8. 04 (bs, 1H), 7.78 (m, 2H), 7.70 (d, J = 8.8 Hz, 1H), 7.66 (m, 2H), 7.60 (d, J = 8. 4 Hz, 1H), 7.58 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.38 (dd, J = 9.2, 4.0, 1H), 7. 32 (bd, J = 7.6 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 3.91 (bd, J = 12.4 Hz, 2H) , 3.69 (m, 1H), 3.61 (bd, J = 10.8 Hz, 2H), 3.48 (m, 1H), 3.21 (m, 4H), 1.31 (t, J _{= 7.2Hz, 3H); C 30} H 29 F 3 N 8 O for the ^{MS (EI): 575.3 (MH} +).

N- (1,1-dimethylethyl) -N′-4- {3- [5- (4-ethylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-3-yl } Phenyl) urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.67 (d, J = 9.2 Hz, 1H), 7.65 (m, 2H), 7.50 (m, 2H) , 7.43 (s, 1H), 7.34 (dd, J = 9.2, 2.0 Hz, 1H), 7.16 (d, J = 2.0, 1H), 3.89 (bd, J = 9.2 Hz, 2H), 3.60 (bd, J = 8.8 Hz, 2H), 3.17 (m, 6H), 1.29 (t, J = 7.2 Hz, 3H), 1. _{27 (s, 9H); C} 27 H 34 N 8 O for the ^{MS (EI): 487.3 (MH} +).

(Example 10)
(2- (5-Phenyl-1H-pyrazol-3-yl) -1H-benzimidazole)

To a solution of methyl (2Z) -3-hydroxy-3-phenylprop-2-enoate: acetophenone (10.0 g, 83.2 mmol) and dimethyl oxalate (11.8 g, 100.0 mmol) in DMF (80 ml), Sodium hydride (4.0 g, 100 mmol, 60% oil dispersion) was added. The mixture was stirred at room temperature for 1 hour and reacted at 50 ° C. for 30 minutes. It was cooled in an ice bath, quenched with water saturated with sodium chloride and neutralized with 2N hydrochloric acid. The organic layer was separated and dried over sodium sulfate. After flash column chromatography (30% ethyl acetate / hexane), the product was obtained as a colorless solid (12.0 g, 70.2% yield): MS (EI) for C ₁₁ H ₁₀ O ₄ : 207.06 (MH ^<+> ).

To a solution of methyl 3-phenyl-1H-pyrazole-5-carboxylate: 2-hydroxy-4-oxo-4-phenyl-but-2-enoic acid methyl ester (12.0 g, 58.2 mmol) in EtOH (30 ml) Hydrazine monohydrate (2.84 ml, 58.2 mmol) was added and the mixture was heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and filtered in vacuo. The precipitate was washed with EtOH to give the desired product (6.02 g, 51.5% yield): MS (EI) for C ₁₁ H ₁₀ N ₂ O ₂ : 203.08 (MH ⁺ ) .

3-Phenyl-1H-pyrazole-5-carboxylic acid: To a solution of methyl 3-phenyl-1H-pyrazole-5-carboxylate (6.02 g, 29.8 mmol) in THF and H ₂ O (3: 1, 140 ml). , LiOH (3.42 g, 142.8 mmol) was added and the mixture was stirred at room temperature overnight. It was poured into 2N HCl solution (150 ml) and extracted with ethyl acetate. After extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product (3.2 g, 57.1%): for C ₁₀ H ₈ N ₂ O ₂ MS (EI): 189.26 (MH ^<+> ).

  N- (2-aminophenyl) -3-phenyl-1H-pyrazole-5-carboxamide: 1,2-diaminobenzene (0.141 g, 1.31 mmol), 3-phenyl-1H-pyrazole-5-carboxylic acid ( To a solution of 188 mg, 1.0 mmol) and HOBT (203 mg, 1.5 mmol) in anhydrous DMF (5 ml) was added EDCI (288 mg, 1.5 mmol). The reaction was stirred at room temperature under nitrogen. After 12 hours, the reaction was concentrated in vacuo and precipitated from methanol with a small amount of water. The solid was collected by vacuum filtration and further purified by reverse phase HPLC (which uses a water-acetonitrile gradient (0.1% TFA)) to give the corresponding amide (60 mg, 38% yield). It was.

2- (3-Phenyl-1H-pyrazol-5-yl) -1H-benzimidazole: A sealed tube filled with a solution of this amide (60 mg, 0.38 mmol) in xylene (1.0 ml) was charged with glacial acetic acid (1. 0 ml) was added and heated to 100 ° C. After 12 hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase HPLC, which uses a water-acetonitrile gradient (0.1% TFA) to give the title benzimidazole (26 mg, 25% yield) as a white solid: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 13.76 (d, 1H), 12.90 (s, 1H), 7.87 (m, 2H), 7.52 (m, 4H), 7. 41 (m, 1H), 6.94 (m, 1H), 7.33 (s, 1H), 7.20 (m, 2H); MS for _{C 16 H 12 N 4 (EI} ): 261.2 (MH ⁺ ).

(Example 11)
(N- {4- [3- (1H-Benzimidazol-2-yl) -1H-pyrazol-5-yl] phenyl} -N′-phenylurea)

(2Z) -3- [4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) phenyl] -3-hydroxyprop-2-enoic acid: dimethyl oxalate (2.73 g, 23. 1 mmol) and 1,1-dimethylethyl (4-acetylphenyl) carbamate (N-BOC-4-aminoacetophenone, 5.44 g, 23.1 mmol) in anhydrous DMF (50 ml) at 0 ° C. with NaH ( 60% dispersion, 2.22 g, 55.5 mmol) was added. The reaction mixture was warmed to room temperature overnight, quenched with saturated aqueous NH ₄ Cl, and neutralized with 1M HCl. The reaction was diluted with ethyl acetate (80 ml) and the organic layer was washed successively with saturated aqueous NaHCO ₃ and brine. The organic phase was separated, dried over Na ₂ SO ₄ , filtered, concentrated in vacuo, and triturated with chloroform to give the condensation product (3.77 g, 53.1% yield). .

To a suspension of the above product (3.27 g, 13.89 mmol) in absolute ethanol (46 ml), 3- [4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) phenyl] -1H— Pyrazole-5-carboxylic acid: hydrazine monohydrate (0.696 g, 13.89 mmol) was added. The reaction mixture was refluxed for 1 hour. The reaction mixture was cooled to room temperature and filtered to give the desired product (2.76, 65.5% yield): ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.44 ( s, 1H), 7.68 (d, 2H), 7.48 (d, 2H), 6.88 (s, 1H), 1.48 (s, 9H).

  [4- (5-{[(2-Aminophenyl) amino] carbonyl} -1H-pyrazol-3-yl) phenyl] carbamate 1,1-dimethylethyl: 1,2-diaminobenzene (0.28 g, 2 .58 mmol), 3- [4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) phenyl] -1H-pyrazole-5-carboxylic acid (0.392 g, 1.29 mmol) and HOBt (0 EDCI (0.372 g, 1.94 mmol) was added to a solution of .262 g, 1.94 mmol) in anhydrous DMF (13 ml). The reaction was stirred at room temperature under nitrogen. After 12 hours, the reaction was concentrated in vacuo and precipitated from methanol with a small amount of water. The solid was collected by vacuum filtration and charged to the next step.

{4- [5- (1H-Benzimidazol-2-yl) -1H-pyrazol-3-yl] phenyl} carbamate 1,1-dimethylethyl: sealed with the amide in xylene (10.0 ml) To the tube was added glacial acetic acid (1.0 ml) and heated to 100 ° C. After 12 hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase HPLC, which uses a water-acetonitrile gradient (0.1% TFA) to give 40 mg of product (29% yield over 2 steps) as a white solid. : ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.62 (s, 1H), 7.74 (m, 4H), 7.61 (m, 2H), 7.45 (s, 2H) _{, 7.35 (s, 1H);} C 21 H 21 N 5 for _{O 2} in ^{MS (EI): 376.2 (MH} +).

  4- [5- (1H-Benzimidazol-2-yl) -1H-pyrazol-3-yl] aniline: {4- [5- (1H-Benzimidazol-2-yl) -1H-pyrazol-3-yl ] To a solution of 1,1-dimethylethyl phenyl} carbamate (130 mg, 0.266 mmol) in methanol (9.0 ml) was added a 4M dioxane (3 ml) solution of hydrochloric acid. The reaction mixture was evaporated in vacuo and triturated with ethyl acetate to give the product as the hydrochloride salt (95.2 mg, 88% yield).

N- {4- [3- (1H-benzoimidazol-2-yl) -1H-pyrazol-5-yl] phenyl} -N′-phenylurea: 4- [3- (1H-benzoimidazol-2-yl) ) -1H-pyrazol-5-yl] aniline (20 mg, 0.064 mmol) and phenyl isocyanate (7.6 mg, 0.064 mmol) in anhydrous acetonitrile (1.0 ml) at room temperature at room temperature with triethylamine (35 μL). 0.25 mmol). After 12 hours, the reaction was concentrated in vacuo and purified by reverse phase HPLC (using a water-acetonitrile gradient (0.1% TFA)) to give the title compound as a white solid ( 9 mg, 36% yield) was obtained: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.08 (s, 1H), 8.92 (s, 1H), 7.78 (m, 4H) , 7.63 (m, 2H), 7.48 (m, 4H), 7.40 (s, 1H), 7.30 (m, 2H), 7.00 (m, 1H); C ₂₃ H ₁₈ MS of the _{N 6 O (EI): 395.2} (MH +).

The following compounds of the invention were prepared using the same or similar synthetic techniques and / or replacing with alternative reagents:
N- {4- [3- (1H-Benzimidazol-2-yl) -1H-pyrazol-5-yl] phenyl} -N ′-[4-chloro-3- (trifluoromethyl) phenyl] urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.58 (s, 1H), 9.38 (s, 1H), 8.16 (s, 1H), 7.80 (m, 4H), 7. 66 (m, 4H), 7.53 (m, 2H), 7.45 (s, 1H); C 24 H 16 N 6 oF 3 for Cl of ^{MS (EI): 497.1 (MH} +).

N- {4- [3- (1H-Benzimidazol-2-yl) -1H-pyrazol-5-yl] phenyl} -N ′-[2-fluoro-5- (trifluoromethyl) phenyl] urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.73 (s, 1H), 9.14 (d, 1H), 8.64 (dd, 1H), 7.81 (m, 4H), 7. 67 (m, 2H), 7.54 (m, 3H), 7.50 (s, 1H); 7.42 (m, 1H): MS for _{C 24 H 16 N 6 oF 4} (EI): 481 .1 (MH ⁺ ).

(Example 12)
(N- (4- {3- [5- (4-Methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) -N ′-{4- [(Trifluoromethyl) oxy] phenyl} urea)

[4- (5-{[Methyl (methyloxy) amino] carbonyl} -1H-pyrazol-3-yl) phenyl] carbamate 1,1-dimethylethyl: N, O-dimethylhydroxyamine hydrochloride (0.87 g , 8.9 mmol), 3- [4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) phenyl] -1H-pyrazole-5-carboxylic acid (2.7 g, 8.9 mmol) and HOBt To a solution of (1.804 g, 13.35 mmol) in anhydrous DMF (30 ml) was added EDCI (2.56 g, 13.35 mmol). The reaction was stirred at room temperature under nitrogen. After 12 hours, the reaction was concentrated under reduced pressure, diluted with ethyl acetate (200 ml) and washed with water. The organic layer was concentrated to give a crude product (2.46 g, yield 80%).

To a suspension of [4- (5-formyl-1H-pyrazol-3-yl) phenyl] carbamate 1,1-dimethylethyl: lithium aluminum hydride (0.889 g, 23.44 mmol) in THF (50 ml), 1,4-Dimethylethyl [4- (5-{[methyl (methyloxy) amino] carbonyl} -1H-pyrazol-3-yl) phenyl] carbamate (2.46 g, 7.1 mmol) at −78 ° C. Of THF (20 ml) was added. After the addition, the reaction mixture was stirred at −78 ° C. for 30 minutes. The reaction mixture was then warmed to room temperature overnight. The reaction was quenched with 30% aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the desired product (1.5 g, 74% yield).

  4- {5- [6- (4-Methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-3-yl} aniline: 4- (4-methylpiperazin-1-yl ) -Benzene-1,2-diamine (as tetrahydrochloride) in anhydrous DMF (11 ml), triethylamine (2.32 g, 23 mmol) was added and after 5 minutes the diamine was [4- (5-formyl -1H-pyrazol-3-yl) phenyl] carbamate 1,1-dimethylethyl in anhydrous DMF (2 ml) was added. The reaction flask was left open to the atmosphere and heated to 65 ° C. After 12 hours, the reaction was concentrated in vacuo and the residue was purified by reverse phase HPLC, which uses a water-acetonitrile gradient (0.1% TFA) to give the product (0.60 g Yield 70%). (Note that the BOC group was removed under this purification condition).

N- (4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) -N ′-{4- [ (Trifluoromethyl) oxy] phenyl} urea: 4- {5- [6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-3-yl} aniline ( 45 mg, 0.12 mmol) in DMSO (2 ml) at room temperature with 1-isocyanato-4-trifluoromethoxybenzene (36.6 mg, 0.18 mmol), triethylamine (36.4 mg, 0.36 mmol) (CH ₃ CN (in 1 ml) was added. The reaction mixture was monitored by LC-MS until the reaction was complete (1 hour). The resulting mixture was concentrated in vacuo and separated by preparative HPLC (0.1% TFA / CH ₃ CN, 0.05% TFA / water). Corresponding fractions were concentrated and dried. The resulting solid was dissolved in MeOH (1 ml) and 4N HCl (0.5 ml) was added. The solution was concentrated and repeated three times to give the product (24%, 34.7 mg) as a light yellow solid as the hydrochloride salt: ¹ H NMR (400 MHz, DMSO-d6): δ 11. 07 (s, 1H), 9.68 (d, 2H), 7.79-7.57 (7H, m), 7.38-7.29 (m, 3H), 7.17 (s, 1H) , 3.90 (m, 2H), 3.46 (m, 2H), 3.21 (m, 4H), 2.85 (m, 3H): C 29 H 27 F 3 N 8 MS for _{O 2} (EI): 577.3 (MH ^<+> ).

The following compounds of the invention were prepared using the same or similar synthetic techniques and / or replacing with alternative reagents:
N- (4- {3- [5- (4-Methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) -N′-phenylurea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.90 (bs, 1H), 9.51 (s, 1H), 9.29 (s, 1H), 7.77 (d, 2H), 7. 70 (d, 1H), 3.91 (m, 2H), 3.69 (m, 2H), 3.19 (m, 4H), 2.86 (s, 3H); C ₂₈ H ₂₈ N ₈ O MS (EI) for: 493.2 (MH ^<+> ).

N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl]- 1H-pyrazol-5-yl} phenyl) urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.41 (bs, 1H), 9.67 (s, 1H), 9.46 (s, 1H ), 8.13 (s, 1H), 7.57 (d, 2H), 7.64 (m, 5H), 7.45 (s, 1H), 7.31 (d, 1H), 7.13 (1H), 3.89 (d, 2H), 3.55 (m, 2H), 3.16 (m, 4H), 2.86 (s, 3H); C ₂₉ H ₂₆ ClF ₃ N ₈ O MS (EI): 595.2 (MH ^<+> ).

N- (2,4-difluorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole-5 Yl} phenyl) urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.87 (bs, 1H), 9.71 (s, 1H), 8.80 (s, 1H), 8.05 ( m, 1H), 7.75 (d, 2H), 7.67 (d, 1H), 7.63 (d, 2H), 7.54 (s, 1H), 7.31 (m, 2H), 7.14 (m, 1H), 7.05 (m, 1H), 3.89 (d, 2H), 3.69 (m, 2H), 3.22 (m, 4H), 2.66 (s) _{, 3H); C 28 H 26} F 2 N 8 O MS for ^{(EI): 529.2 (MH +} ).

N- [3,4-bis (methyloxy) phenyl] -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H— Pyrazol-5-yl} phenyl) urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.43 (bs, 1 H), 9.16 (s, 1 H), 8.88 (s, 1 H), 7.75 (d, 2H), 7.69 (d, 1H), 7.64 (d, 2H), 7.47 (s, 1H), 7.36 (d, 1H), 7.24 (s , 1H), 7.17 (s, 1H), 6.89 (s, 1H), 3.92 (d, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 3 .56 (d, 2H), 3.22 (d, 2H), 3.17 (d, 2H), 2.87 (d, 3H); C ₃₀ H ₃₂ N ₈ O ₃ MS (EI): 553.3 (MH ^<+> ).

N- (4- {3- [5- (4-Methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) -N ′-[3- ( Trifluoromethyl) phenyl] urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.81 (bs, 1 H), 9.74 (s, 1 H), 9.62 (s, 1 H), 8. 02 (s, 1H), 7.76 (d, 2H), 7.65 (m, 3H), 7.58 (d, 1H), 7.52 (m2H), 7.32 (m, 2H), 7.14 (s, 1H), 3.92 (d, 2H), 3.58 (d, 2H), 3.24 (m, 4H), 2.84 (d, 3H); C ₂₉ H ₂₇ F ₃ N ₈ O MS for ^{(EI): 561.3 (MH +} ).

N- (4-chlorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} phenyl ) Urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.58 (bs, 1H), 9.40 (s, 1H), 9.35 (s, 1H), 7.70 (d, 2H) ), 7.68 (d, 1H), 7.64 (d, 2H), 7.51 (d, 2H), 7.49 (d, 1H), 7.34 (m, 3H), 7.16 (S, 1H), 3.91 (d, 2H), 3.55 (d, 2H), 3.17 (m, 4H), 2.86 (d, 3H); C ₂₈ H ₂₇ ClN ₈ O MS (EI): 527.2 (MH ^<+> ).

N- (4-fluorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.92 (bs, 1H), 9.50 (s, 1H), 9.36 (s, 1H), 7.76 (d, 2H), 7.69 (d, 1H), 7.64 (d, 2H), 7.55 (s, 1H), 7.49 (dd, 1H), 7.37 (dd, 1H), 7. 15 (d, 2H), 7.12 (s, 1H), 3.91 (d, 2H), 3.55 (d, 2H), 3.17 (m, 4H), 2.86 (d, 3H) _{); C 28 H 27 FN 8} O for the ^{MS (EI): 511.3 (MH} +).

N- (3-fluorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.92 (bs, 1H), 9.63 (s, 1H), 9.62 (s, 1H), 7.83 (d, 2H), 7.68 (d, 1H), 7.65 (d, 2H), 7.53 (m, 2H), 7.34 (dd, 2H), 7.17 (s, 1H), 7. 13 (d, 1H), 6.80 (m, 1H), 3.90 (d, 2H), 3.69 (m, 2H), 3.23 (m, 4H), 2.84 (s, 3H) _{); C 28 H 27 FN 8} O for the ^{MS (EI): 511.3 (MH} +).

N- (2-fluorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.14 (bs, 1H), 9.91 (s, 1H), 8.90 (s, 1H), 8.15 (t, 1H), 7.79 (d, 2H), 7.68 (m, 3H), 7.61 (s, 1H), 7.37 (d, 1H), 7.25 (dd, 1H), 7. 16 (m, 2H), 7.03 (m, 1H), 3.54 (m, 2H), 3.48 (m, 2H), 3.21 (m, 4H), 2.84 (s, 3H _{); C 28 H 27 FN 8} O for the ^{MS (EI): 511.3 (MH} +).

N- (3,4-dichlorophenyl) -N '-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl } Phenyl) urea: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.05 (bs, 1H), 9.91 (s, 1H), 9.77 (s, 1H), 7.90 (d , 1H), 7.78 (d, 2H), 7.69 (d, 1H), 7.64 (d, 2H), 7.58 (s, 1H), 7.54 (d, 1H), 7 .36 (dt, 2H), 7.16 (s, 1H), 3.90 (d, 2H), 3.53 (m, 2H), 3.20 (m, 4H), 2.84 (d, _{3H); C 28 H 26 Cl} 2 N 8 O for the ^{MS (EI): 561.2 (MH} +).

N- (4- {3- [5- (4-Methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) -N ′-[4- ( Phenyloxy) phenyl] urea: ¹ H NMR (400 MHz, CD ₃ OD): δ 7.67-7.61 (m, 3H), 7.55-7.52 (m, 2H), 7.45-7 .42 (m, 2H), 7.37-7.30 (m, 3H), 7.24 (m, 1H), 7.19 (s, 1H), 7.09-7.05 (m, 1H) ), 6.97-6.93 (m, 4H), 3.95-3.89 (d, 2H), 3.75-3.71 (m, 1H), 3.68-3.63 (m , 3H), 3.59-3.56 (m, 1H), 3.23-3.15 (m, 2H), 2.97 (s, 3H); C ₃₄ H ₃₂ N ₈ O MS (EI) for ₂ : 585.3 (MH ^<+> ).

N- (3,5-difluorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole-5 Yl} phenyl) urea: ¹ H NMR (400 MHz, CD ₃ OD): δ (m, 3H), 7.64-7.61 (m, 2H), 7.43-7.40 (m, 1H), 7.31-7.29 (m, 2H), 7.15-7.12 (m, 2H), 6.60-6.54 (m, 1H), 4.01-3.94 (d, 2H) ), 3.71-3.65 (m, 2H), 3.39-3.32 (m, 1H), 3.25-3.17 (m, 3H), 3.01 (s, 3H); _{C 28 H 26 F 2 N 8} O MS for ^{(EI): 529.2 (MH +} ).

N- [3,5-bis (trifluoromethyl) phenyl] -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H -Pyrazol-5-yl} phenyl) urea: ¹ H NMR (400 MHz, CD ₃ OD): δ 8.11 (s, 2H), 7.75-7.64 (m, 5H), 7.56 (m , 5H), 7.43-7.39 (dd, 1H), 7.30 (s, 2H), 4.01-3.94 (d, 2H), 3.75-3.64 (m, 4H) ), 3.25-3.17 (m, 2H) , 3.01 (s, 3H); C 30 H 26 F 6 N 8 O for the ^{MS (EI): 629.2 (MH} +).

N- (3-chlorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} phenyl ) Urea: ¹ H NMR (400 MHz, CD ₃ OD): δ 7.73-7.66 (m, 4H), 7.63-7.60 (m, 2H), 7.43-7.40 (m) , 1H), 7.30-7.25 (m, 4H), 7.04-7.00 (m, 1H), 4.00-3.94 (d, 2H), 3.70-3.65 (m, 2H), 3.39-3.33 ( m, 2H), 3.25-3.16 (m, 2H), 3.00 (s, 3H); for _{C 28} H 27 ClN ₈ O of MS (EI): 527.2 (MH ^&lt; ^{+ &gt;} ).

N- [3- (methyloxy) phenyl] -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole-5 -Yl} phenyl) urea: ¹ H NMR (400 MHz, CD ₃ OD): δ 7.65-7.62 (d, 1H), 7.58-7.55 (d, 2H), 7.49-7 .45 (d, 2H), 7.35-7.31 (m, 1H), 7.20-7.13 (m, 4H), 6.95 (6.92 (m, 1H0, 6.61-) 6.58 (m, 1H), 3.92-3.87 (d, 2H), 3.79 (s, 3H), 3.68-3.60 (m, 2H), 3.28-3. 13 (m, 4H), 2.94 (s, 3H); C 29 H 30 N 8 MS for _{O 2 (EI): 523.3 (} MH +).

N- (3-acetylphenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea: ¹ H NMR (400 MHz, CD ₃ OD): δ 7.72-7.57 (m, 8H), 7.46-7.38 (m, 2H), 7.29-7.26 ( m, 2H), 4.00-3.93 (m, 2H), 3.70-3.64 (m, 4H), 3.25-3.17 (m, 2H), 3.00 (s, _{3H), 2.61 (s, 3H} ); C 30 H 30 N 8 MS for _{O 2 (EI): 535.3 (} MH +).

N- (3,4-difluorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole-5 Yl} phenyl) urea: ¹ H NMR (400 MHz, CD ₃ OD): δ 7.73-7.69 (m, 3H), 7.63-7.58 (m, 3H), 7.43-7. 40 (m, 1H), 7.31-7.29 (m, 2H), 7.22-7.15 (m, 1H), 7.10-7.05 (m, 1H), 4.00- 3.94 (d, 2H), 3.71-3.56 (m, 3H), 3.40-3.33 (m, 1H), 3.25-3.16 (m, 2H), 3. _{00 (s, 3H); C} 28 H 26 F 2 N 8 O for the ^{MS (EI): 529.2 (MH} +).

N- [4-Fluoro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl]- 1H-pyrazol-5-yl} phenyl) urea: ¹ H NMR (400 MHz, CD ₃ OD): δ 7.95-7.91 (m, 1H), 7.74-7.62 (m, 6H), 7.44-7.40 (m, 1H), 7.31-7.25 (m, 3H), 4.01-3.94 (d, 2H), 3.71-3.56 (m, 3H) ), 3.40-3.32 (m, 1H) , 3.26-3.16 (m, 2H), 3.01 (s, 3H); C 29 H 26 F 4 N 8 O MS for ( EI): 579.2 (MH ^<+> ).

N- [3,5-bis (methyloxy) phenyl] -N ′-(4- {3- [6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H— Pyrazol-5-yl} phenyl) urea: ¹ H NMR (400 MHz, d-MeOH): δ 7.70 (m, 3H), 7.60 (d, 2H), 7.41 (d, 1H), 7 .24 (m, 2H), 6.70 (d, 2H), 6.22 (s, 1H), 3.86 (brd, 2H), 3.78 (s, 6H), 3.62 (br d, 2H), 3.30 (m , 4H), 3.02 (s, 3H); C 30 H 32 N 8 O 3 MS for ^{(EI): 590 (MH +} ).

N- (3-bromophenyl) -N ′-(4- {3- [6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea: ¹ H NMR (400 MHz, d-MeOH): δ 7.82 (br t, 1H), 7.72 (br d, 3H), 7.62 (br d, 2H), 7.42 ( dd, 1H), 7.35 (m, 3H), 7.18 (m, 2H), 3.90 (brd, 2H), 3.78 (s, 6H), 3.63 (brd, 2H) ), 3.34 (m, 4H) , 3.08 (s, 3H); C 28 H 27 BrN 8 O MS for ^{(EI): 573 (MH +} ).

N- (3-cyanophenyl) -N ′-(4- {3- [6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea: ¹ H NMR (400 MHz, d-MeOH): δ 8.02 (brs, 1H), 7.61 (m, 6H), 7.51 (t, 1H), 7.34 (m, 4H), 3.90 (br s, 2H), 3.62 (br s, 2H), 3.25 (m, 4H), 3.04 (s, 3H); C ₂₉ H ₂₇ N ₉ O MS (EI): 518 (MH ^<+> ).

N- (5-fluoro-2-methylphenyl) -N ′-(4- {3- [6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole- 5-yl} phenyl) urea: ¹ H NMR (400 MHz, d-MeOH): δ 7.72 (m, 5H), 7.40 (d, 1H), 7.31 (d, 2H), 7.20 (T, 1H), 6.72 (t, 1H), 3.98 (brd, 2H), 3.68 (brd, 2H), 3.26 (m, 4H), 3.02 (s, _{3H); C 29 H 29 FN} 8 O for the ^{MS (EI): 523 (MH} +).

N- (4- {3- [6- (4-Methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) -N ′-[4- ( Trifluoromethyl) phenyl] urea: ¹ H NMR (400 MHz, d-MeOH): δ 7.71 (m, 3H), 7.64 (m, 3H), 7.62 (m, 3H), 7.42 (Br d, 1H), 7.29 (m, 2H), 3.92 (d, 2H), 3.72 (d, 2H), 3.32 (m, 4H), 3.04 (s, 3H ); MS (EI) for C ₂₉ H ₂₇ FN ₈ O: 561 (MH ⁺ ).

(Assay)
Kinase assays were performed by .gamma. ^{33 P} incorporation measurements of ATP into immobilized myelin basic protein (MBP). High binding white 384 well plates (Greiner) were transferred to 20 μg / ml MBP in Tris-buffered saline (TBS; 50 mM Tris (pH 8.0), 138 mM NaCl, 2.7 mM KCl) at 4 ° C. for 24 hours. Coat with MBP (Sigma # M-1891) by incubation at 60 μl / well. The plate was washed 3 times with 100 μl TBS. The kinase reaction kinase buffer (5mM Hepes (pH 7.6), 15mM NaCl, 0.01% bovine γ-globulin _{(Sigma # I-5506),} 10mM MgCl 2, 1mM DTT, 0.02% TritonX-100) In, in a total volume of 34 μl. Compound dilutions were performed in DMSO and added to assay wells to a final DMSO concentration of 1%. Each data point was measured repeatedly and at least two duplicate assays were performed for each individual compound measurement. Enzymes were added, for example, to a final concentration of 10 nM or 20 nM. Mixture of unlabeled ATP and γ- ³³ P ATP (typically 2 × 10 ⁶ cpm γ- ³³ P ATP (3000 Ci / mmole) per well and either 10 μM or 30 μM unlabeled ATP Was added to initiate the reaction. The reaction was carried out with shaking at room temperature for 1 hour. Plates were washed 7 times with TBS, followed by addition of 50 μl / well scintillation fluid (Wallac). Plates were read using a Wallac Trilux counter. This is just one type of assay format, and various other formats are possible in the art.

The assay procedure can be used to determine the IC ₅₀ and / or inhibition constant (K _i ) for inhibition. IC ₅₀ is determined as the concentration of compound required to reduce enzyme activity by 50% under the above assay conditions. Exemplary compositions have, for example, an IC ₅₀ of less than about 100 μM, less than about 10 μM, less than about 1 μM, and further have, for example, an IC ₅₀ of less than about 100 nM, and still further, for example, about Less than 10 nM. The K _i for a compound can be determined from the IC ₅₀ based on three assumptions. First, only one compound molecule binds to the enzyme and there is no cooperativity. Second, the concentration of active enzyme and the compound being tested are known (ie, there is no significant amount of impurities or inactive forms in the preparation). Third, the enzyme-inhibitor complex has a zero enzymological rate. The above rate (ie, compound concentration) data was fit to the following equation (1); where V is the observed rate, V _max is the rate of free enzyme, and I ₀ is the inhibitor concentration. , E ₀ is the enzyme concentration and K _d is the dissociation constant of the enzyme-inhibitor complex.

.

(Kinase specific assay)
Kinase activity and compound inhibition were studied using one or more of the three assay formats described below. The ATP concentration for each assay is selected to be close to the Michaelis-Menten constant (K _M ) for each individual kinase. Dose response experiments are performed at 10 different inhibitor concentrations in a 384 well plate format. This data was fitted to the following four parameter equations (2); where Y is the observed signal, X is the inhibitor concentration, and Min is the back in the absence of enzyme (0% enzyme activity). Ground signal, Max is signal in the absence of inhibitor (100% enzyme activity), IC ₅₀ is inhibitor concentration at 50% enzyme inhibition, and H is experimental Hills to measure cooperativity. Represents a slope (Hill's slope). Typically, H approaches 1.

.

⁽³³ P phosphoryl transfer assay)
White, clear bottom Greiner 384 well high binding plates are coated overnight with 50 μL volume of 2 μg / well protein or peptide substrate at ambient temperature. The coating buffer typically contains 40 μg / mL substrate, 22.5 mM Na ₂ CO ₃ , 27.5 mM NaHCO ₃ , 150 mM NaCl and 3 mM NaN ₃ . The coating solution was aspirated and the plate was washed once with 50 μL of assay buffer and wiped dry. Compounds and enzymes were then mixed with γ ³³ P-ATP (3.3 Ci / nmol) in a total volume of 20 uL in the appropriate assay buffer. The mixture was incubated at ambient temperature for 1.5-2.5 hours and terminated by aspiration using a Molecular Devices EMBLA 96 headplate washer. The plate was then washed 6-12 times with PBST or TBS buffer. Scintillation fluid (50 μl / well) was then added, the plates were sealed and activity was assessed by liquid scintillation spectroscopy using a Perkin Elmer MicroBeta TriLux.

(Luciferase-coupled chemiluminescence assay (LCCA))
In the LCCA assay, kinase activity was measured as% of ATP consumed after the kinase reaction using luciferase-luciferin-coupled chemiluminescence. A white, clear bottom Greiner 384 well medium binding plate is used for LCCA. Briefly, the kinase reaction was initiated by mixing compound, ATP and kinase in a 20 uL volume. This mixture was incubated at ambient temperature for 2-4 hours. At the end of the kinase reaction, 20 uL of luciferase-luciferin mix (mix) is added and the chemiluminescent signal is read using a Wallac Victor ² reader. The luciferase-luciferin mix consists of 50 mM HEPES (pH 7.8), 8.5 ug / mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100, 0 Consists of 25 mg / mL coenzyme A, 63 uM AMP, 28 ug / mL luciferin and 40,000 units of light luciferase per mL. For the LCCA assay, the total consumption of ATP is normalized to 25-45%, and the IC ₅₀ value correlates well with the value measured by the radiometric assay.

(AlphaScreen)
AlphaScreen technology is a proximity assay that takes advantage of the increase in fluorescent signal that occurs when donor and acceptor beads are in close proximity. Biotinylated poly (Glu, Tyr) 4: 1 is used as a substrate for the kinase with streptavidin-coated donor beads and anti-phosphotyrosine antibody PY100-coated acceptor beads. Upon phosphorylation, the peptide substrate can bind to both donor and acceptor beads and generate an increase in fluorescence. Compound, ATP, biotinylated poly (Glu, Tyr) and kinase are mixed in a volume of 20 uL for 1 hour at ambient temperature using a white, clear bottom Greiner 384 well medium binding plate. After incubation, a 10 uL solution containing 15-30 mg / mL AlphaScreen beads, 75 mM Hepes (pH 7.4), 300 mM NaCl, 120 mM EDTA, 0.3% BSA and 0.03% Tween-20, Add to each well. After 2-16 hours incubation of the beads, the plate is read in a Perkin Elmer AlphaQuest reader. IC ₅₀ values correlate well with those of radiometric assays.

(C-Kit assay)
The biochemical activity of c-Kit was assessed using AlphaScreen ^™ (Perkin Elmer) technology, as described above. Test compounds, ATP, biotinylated poly (Glu, Tyr) and c-Kit kinase were mixed in a volume of 20 μL in a white 384 well medium binding microtiter plate (Greiner). The reaction mixture was incubated for 1 hour at ambient temperature. The reaction was performed with 10 uL of 15-30 mg / mL AlphaScreen bead suspension containing 75 mM Hepes (pH 7.4), 300 mM NaCl, 120 mM EDTA, 0.3% BSA and 0.03% Tween-20. Was quenched by the addition of After 16 hours incubation at ambient temperature, the plates were read using an AlphaQuest reader (Perkin Elmer).

(Flt-3 assay)
The biochemical activity of flt-3 was assessed using a luciferase-coupled chemiluminescence assay (LCCA) format. Kinase activity was measured as the percent of ATP remaining after the kinase reaction. Residual ATP was detected by luciferase-luciferin-coupled chemiluminescence. Specifically, the reaction was performed using a test compound, 5 μM ATP, 3 μM poly-EY and 5 nM Flt-3 (human Flt-3 kinase domain R571-S993 expressed by baculovirus) in 20 uL assay buffer. liquid (Tris-HCL (pH7.5 in 20 mM), 10 mM of MgCl _2, 0.01% of Triton X-100, 1 mM of DTT, MnCl ₂ of 2 mM) was initiated by mixing in. The mixture is incubated for 3 hours at ambient temperature after addition of 20 uL luciferase-luciferin mix and the chemiluminescent signal is read using a Wallac Victor ² reader. The luciferase-luciferin mix consists of 50 mM HEPES (pH 7.8), 8.5 ug / mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100, 0 Consists of 25 mg / mL coenzyme A, 63 uM AMP, 28 ug / mL luciferin and 40,000 units of light luciferase per mL.

(Structure-activity relationship)
Table 2 shows structure activity relationship data for exemplary compounds of the invention. Inhibit, shown as _{IC 50} with the following symbol (key): A = _IC 50 less than 50 nM, B = 50 nM larger the _IC 50 of less than 500 nM, C = 500 nM larger the _{IC 50} of less than 5000nM and, IC _{50 with} D = 5,000 nM or more. A blank cell indicates only the lack of data. Abbreviations for the enzymes listed in Table 2 are defined as follows: c-Kit is also referred to as stem cell factor receptor or steel factor receptor; flt-3 refers to fms-like tyrosine kinase-3 EphB4 refers to ephrin receptor tyrosine kinase family member B4; and EGFR refers to epidermal growth factor receptor tyrosine kinase.

Claims (32)

A compound according to Formula I that modulates kinase activity, or a pharmaceutically acceptable salt or hydrate thereof:
here,
Each of R ¹ and R ² is independently haloC ₁ -C ₈ alkyl, haloC ₁ -C ₈ alkoxy, —N (R ³ ) C (═O) N (R ³ ) R ³ , —N ( R ³ ) C (═O) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (O) ₂ R ³ , optionally substituted C ₆ -C ₁₄ aryl, optionally Optionally substituted 3-15 membered heterocyclyl, or optionally substituted 3-15 membered heterocyclyl C ₁ -C ₆ alkyl;
each of m and n is independently 1-5;
Each of A and B are independently phenyl, benzothiophenyl, pyridyl, benzofuranyl, Ru is selected from the group consisting of naphthyl and benzimidazolyl;
R ³ is —H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₆ -C ₁₄ aryl, or optionally substituted C ₆ -C ₁₄ aryl C ₁ -C ₆ alkyl;
R ⁴ is —H; and each of L ¹ and L ² is independently selected from absent and —C (R ³ ) ═C (R ³ ) —;
Wherein optionally substituted alkyl, aryl, aryl C ₁ -C ₆ alkyl, heterocyclyl and heterocyclyl C ₁ -C ₆ alkyl, when substituted, are separately one or more substituents Wherein the substituents are independently C ₁ -C ₆ alkyl, C ₁ -C ₈ alkoxy, halo, halo C ₁ -C ₆ alkyl, halo C ₁ -C ₈ alkoxy, -CN,- A compound, salt, or hydrate selected from the group consisting of OR ³ , —N (R ³ ) R ³ , and C ₆ -C ₁₄ aryl. The compound, salt or hydrate according to claim 1, wherein R ⁴ is -H. The compound, salt or hydrate according to claim 2, wherein L ¹ and L ² are both -C (R ³ ) = C (R ³ )-. L ¹ and ^{L 2,} the ^{both, E - C (R 3)} = C (R 3) - in which A compound according to claim 3, a salt or hydrate thereof. A compound, salt or hydrate according to claim 4, which is of formula II,
Here, each of R ¹ and R ² is independently haloC ₁ -C ₈ alkyl, haloC ₁ -C ₈ alkoxy, —N (R ³ ) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (═O) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (O) ₂ R ³ , optionally substituted 3-15 membered heterocyclyl or required is C ₆ -C ₁₄ aryl which is optionally substituted; and each of a and B is a radical, the radical is independently phenyl, benzothiophenyl, pyridyl, benzofuranyl, or naphthyl and benzimidazolyl Ranaru Selected from the group,
Compound, salt or hydrate. 6. A compound, salt or hydrate according to claim 5, which is formula IIa,
Here, each of R ¹ and R ² is independently haloC ₁ -C ₈ alkyl, haloC ₁ -C ₈ alkoxy, —N (R ³ ) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (═O) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (O) ₂ R ³ , optionally substituted 3-15 membered heterocyclyl or Optionally substituted C ₆ -C ₁₄ aryl;
Compound, salt or hydrate. Each of R ¹ and ^{R 2} are, independently, a halo _C 1 -C ₈ alkyl or halo _C 1 -C ₈ alkoxy, A compound according to claim 6, a salt or hydrate thereof. R ¹ is is halo _C 1 -C ₈ alkyl or halo _C 1 -C ₈ alkoxy; and ^{R 2} is -N ^(R 3) compound of Claim 7 is ^{R 3.} L ¹ is absent and ^{L 2 is, -C (R 3) = C} (R 3) - A compound according to claim 2, salt or hydrate thereof. L ¹ is absent and ^{L 2} is, -C (H) = C ( H) - is a compound according to claim 9, a salt or hydrate thereof. A compound, salt or hydrate according to claim 9, which is of formula IV
Here, each of R ¹ and R ² is independently haloC ₁ -C ₈ alkyl, haloC ₁ -C ₈ alkoxy, —N (R ³ ) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (═O) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (O) ₂ R ³ , optionally substituted 3-15 membered heterocyclyl or is C ₆ -C ₁₄ aryl optionally substituted; and each a and B is a radical, the radical is independently phenyl, benzothiophenyl, pyridyl, benzofuranyl, naphthyl and benzimidazolyl or Ranaru group Selected from the
Compound, salt or hydrate. L ² is absent and ^{L 1 is, -C (R 3) = C} (R 3) - in which A compound according to claim 2, salt or hydrate thereof. L ² is absent and ^{L 1} is, -C (H) = C ( H) - is a compound according to claim 12, salt or hydrate thereof. 14. A compound, salt or hydrate according to claim 13 of formula IVa, comprising
Here, each of R ¹ and R ² is independently haloC ₁ -C ₈ alkyl, haloC ₁ -C ₈ alkoxy, —N (R ³ ) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (═O) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (O) ₂ R ³ , optionally substituted 3-15 membered heterocyclyl or is selected from C ₆ -C ₁₄ aryl optionally substituted; and each a and B is a radical, the radical is independently phenyl, benzothiophenyl, pyridyl, benzofuranyl, naphthyl and benzimidazolyl or al Selected from the group
Compound, salt or hydrate. The compound, salt or hydrate of claim 2, wherein L ¹ and L ² are both absent. 16. A compound, salt or hydrate according to claim 15 , selected from the group consisting of:
N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [5- (4-ethylpiperazin-1-yl) -1H-benzimidazol-2-yl]- 1H-pyrazol-5-yl} phenyl) urea;
N- (3-ethylphenyl) -N ′-(4- {3- [5- (4-ethylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea;
N- (4- {3- [5- (4-Ethylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) -N ′-[3- ( Trifluoromethyl) phenyl] urea;
N- (3-acetylphenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea;
N- (3,4-dichlorophenyl) -N '-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl } Phenyl) urea;
N- (3-bromophenyl) -N ′-(4- {3- [6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea;
N- [4-Fluoro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl]- 1H-pyrazol-5-yl} phenyl) urea;
N- (4- {3- [5- (4-Methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) -N ′-[4- ( Phenyloxy) phenyl] urea;
N- (3-chlorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} phenyl )urea;
N- [3,5-bis (methyloxy) phenyl] -N ′-(4- {3- [6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H— Pyrazol-5-yl} phenyl) urea;
N- (4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) -N ′-{4- [ (Trifluoromethyl) oxy] phenyl} urea;
N- (4- {3- [6- (4-Methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) -N ′-[4- ( Trifluoromethyl) phenyl] urea;
N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl]- 1H-pyrazol-5-yl} phenyl) urea;
N- (4- {3- [5- (4-Methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) -N ′-[3- ( Trifluoromethyl) phenyl] urea;
N- (4-chlorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} phenyl )urea;
N- (3,5-difluorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole-5 Il} phenyl) urea;
N- [3- (methyloxy) phenyl] -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole-5 -Yl} phenyl) urea;
N- (3-fluorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea;
N- (4-fluorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea;
N- (3-cyanophenyl) -N ′-(4- {3- [6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea;
N- (3,4-difluorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole-5 Il} phenyl) urea;
N- [3,4-bis (methyloxy) phenyl] -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H— Pyrazol-5-yl} phenyl) urea;
N- (2,4-difluorophenyl) -N ′-(4- {3- [6- (4-ethylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole-5 Il} phenyl) urea;
N- (2,4-difluorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole-5 Il} phenyl) urea;
N- [3,5-bis (trifluoromethyl) phenyl] -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H -Pyrazol-5-yl} phenyl) urea;
N- (2-fluorophenyl) -N ′-(4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} Phenyl) urea;
N- (5-fluoro-2-methylphenyl) -N ′-(4- {3- [6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole- 5-yl} phenyl) urea;
N- (4- {3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazol-5-yl} phenyl) -N′-phenylurea; and N- (1,1-dimethylethyl) -N ′-(4- {3- [5- (4-ethylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyrazole-5 Yl} phenyl) urea. 16. A compound, salt or hydrate according to claim 15 , which is of formula VI,
Here, each of R ¹ and R ² is independently haloC ₁ -C ₈ alkyl, haloC ₁ -C ₈ alkoxy, —N (R ³ ) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (═O) C (═O) N (R ³ ) R ³ , —N (R ³ ) C (O) ₂ R ³ , optionally substituted 3-15 membered heterocyclyl or Optionally substituted C ₆ -C ₁₄ aryl;
Where R ⁶ is —H, halogen, haloC ₁ -C ₈ alkyl, haloC ₁ -C ₈ alkoxy, —CN, —NO ₂ , —OR ³ , or —C (═O) R ³ :
p is 1-5;
A is a radical, the radical is phenyl, benzothiophenyl, pyridyl, or selected benzofuranyl and benzoimidazolyl, et al .; and,
L ³ is absent, — (CH ₂ ) _{0 to 1} N (R ³ ) C (═O) N (R ³ ) —, —N (R ³ ) C (═O) N (R ³ ) (CH _{2) 0~1 -, - (CH} 2) 0~1 N (R 3) CO 2 - or _{^{-N (R 3) CO 2 (}} CH 2) 0~1 - is,
Compound, salt or hydrate. 18. A compound, salt or hydrate according to claim 17 , selected from the group consisting of:
N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} Phenyl) urea;
N- (3,4-dimethylphenyl) -N ′-(4- {5- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-3-yl} phenyl) urea;
N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [4- (4-ethylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} Phenyl) urea;
N- [5-Chloro-2- (methyloxy) phenyl] -N ′-(4- {5- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-3-yl} phenyl )urea;
N- (4- {5- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-3-yl} phenyl) -N ′-[4- (phenyloxy) phenyl] urea;
N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4- {3- [3- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} Phenyl) urea;
N- (2,4-difluorophenyl) -N ′-(4- {3- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} phenyl) urea;
N- (2,3-dihydro-1,4-benzodioxin-6-yl) -N ′-(4- {5- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazole- 3-yl} phenyl) urea;
N- [2,4-bis (methyloxy) phenyl] -N ′-(4- {5- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-3-yl} phenyl) urea;
N- (4- {3- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} phenyl) -N ′-(2-phenylethyl) ethanediamide;
4-((E) -2- {3- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-5-yl} ethenyl) phenol;
N- (5-fluoro-2-methylphenyl) -N ′-(4- {5- [4- (4-methylpiperazin-1-yl) phenyl] -1H-pyrazol-3-yl} phenyl) urea;
4-{(E) -2- [3- (4-chlorophenyl) -1H-pyrazol-5-yl] ethenyl} phenol;
4-{(E) -2- [3- (5-chloro-1-benzofuran-2-yl) -1H-pyrazol-5-yl] ethenyl} phenol;
4-[(E) -2- (3-pyridin-4-yl-1H-pyrazol-5-yl) ethenyl] phenol; and 4-{(E) -2- [3- (3-chlorophenyl) -1H -Pyrazol-5-yl] ethenyl} phenol. When A is phenyl, ^{L 3 is, -N (R 3) C (} = O) N (R 3) - in which A compound according to claim 17, salt or hydrate thereof. 20. A compound, salt or hydrate according to claim 19 , wherein A is either phenyl or benzimidazolyl. 21. A compound, salt or hydrate according to claim 20 , which is either formula VIIa or formula VIIb:
Where R ¹ is halo C ₁ -C ₈ alkyl, halo C ₁ -C ₈ alkoxy, —N (R ³ ) C (O) ₂ R ³ , optionally substituted 3-15 membered heterocyclyl or necessary Optionally substituted C ₆ -C ₁₄ aryl; m is 1-5;
R ² is haloC ₁ -C ₈ alkyl, haloC ₁ -C ₈ alkoxy, or —N (R ³ ) R ³ ;
R ⁶ is —H, halogen, haloC ₁ -C ₈ alkyl, —CN, —NO ₂ , —OR ³ or —C (═O) R ³ ; and p is 1-5.
Compound, salt or hydrate. 22. A compound, salt or hydrate according to claim 21 , wherein the phenylurea in VIIb is in either the meta or para position relative to the pyrazole moiety. 23. A compound, salt or hydrate according to claim 22 , which is either formula VIIc or formula VIId, comprising:
Where R ¹ is haloC ₁ -C ₈ alkyl, haloC ₁ -C ₈ alkoxy, —N (R ³ ) C (O) ₂ R ³ or optionally substituted 3-15 membered heterocyclyl. ;
R ^3a and R ^3b are each independently —H and optionally substituted C ₁ -C ₆ alkyl; or R ^3a and R ^3b are combined together with the nitrogen to which they are attached. Can form optionally substituted heteroalicyclyl, which contains between 1 and 2 additional heteroatoms;
R ⁶ is —H, halogen, haloC ₁ -C ₈ alkyl, —CN, —NO ₂ , —OR ³ or —C (═O) R ³ ;
p is 1-5.
Compound, salt or hydrate. For VIIc, —N (R ^3a ) R ^3b is in either the meta or para position relative to the pyrazole moiety; and the phenylurea in VIId is meta or para relative to the pyrazole moiety. 24. A compound, salt or hydrate according to claim 23 in any of the positions. Table 3:
Or a pharmaceutically acceptable salt or hydrate thereof. 26. A pharmaceutical composition comprising a compound, salt or hydrate according to any one of claims 1 to 25 and a pharmaceutically acceptable carrier. A composition for modulating the in vivo activity of a kinase, comprising an effective amount of at least one compound, salt or hydrate according to any of claims 1 to 25 and a pharmaceutically acceptable carrier. A composition. 28. The composition of claim 27 , wherein the kinase is selected from c-Kit and flt-3. 30. The composition of claim 28 , wherein modulation of the in vivo activity of the kinase comprises inhibition of the kinase. A composition for treating a disease or disorder associated with uncontrolled abnormal and / or unwanted cellular activities, the compounds according to any one of claims 1 to 25 and a salt or hydrate of at least one A composition comprising a therapeutically effective amount and a pharmaceutically acceptable carrier, wherein the disease or disorder is selected from cancer, immunological disorders, cardiovascular diseases, inflammatory diseases and degenerative diseases. A method for screening for a modulator of a kinase, comprising combining at least one compound, salt or hydrate according to any one of claims 1 to 25 with at least one candidate reagent, and the kinase Determining the effect of the candidate reagent on the activity of. A method of inhibiting proliferation activity in a cell or a plurality of cells in vitro, wherein the cell or the plurality of cells are subjected to at least one compound, salt or hydrate according to any one of claims 1 to 25 . A method comprising administering an effective amount.